Inclusion Criteria:

1. Males or females with a suspected or histologically confirmed index oral premalignant lesion (OPL) that has a length (longest diameter) of 8 mm or greater and width (diameter perpendicular to greatest length) of 3 mm or greater in size.
2. Participants with suspected OPL must not have had a biopsy within 6 weeks prior to the Screening biopsy (the 6 week limitation before re-biopsy is to minimize inflammation in study tissue). The Screening biopsy must be histologically confirmed before the second stage of registration can be completed.
3. Participants presenting with histologically confirmed OPL at the Screening visit must have had the diagnostic biopsy within 8 weeks of randomization (or no more than 6 weeks before stage one registration). Adequate archival tissue for biomarker analysis must be available. The pre-Screening biopsy must undergo centralized pathology review before the second stage of registration can be completed. To allow for centralized review, the pre-Screening biopsy must have been performed no more than 6 weeks before the Screening visit.
4. Age >/= 18 years
5. The participant's life expectancy is > 6 months.
6. The participant's ECOG performance status is 0 or 1.
7. The participant has discontinued any other oral cancer chemopreventive therapy, including use of more than one multi-vitamin per day and use of any particular vitamin supplement at >3 times the United States Dietary Reference Intake (DRI) [Recommended Dietary Allowance (RDA) or Adequate Intake (AI) as applicable) (see Appendix B) at least 12 weeks prior to the Baseline visit and all toxicities have been fully resolved. Daily aspirin is permitted.
8. The participant is willing and able to fully participate for the duration of the study.
9. The effects of pioglitazone on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women must not be pregnant or lactating. Women of child-bearing potential (women are considered not of childbearing potential if they are at least two years postmenopausal and/or surgically sterile) must have used adequate contraception (abstinence; barrier methods such as IUD, diaphragm with spermicidal gel, condom, or others; and hormonal methods such as birth control pills or others) since her last menses prior to study entry.
10. Continuation of Inclusion 9.) Women of child-bearing potential and men must agree to use adequate contraception for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.
11. Ability to understand and the willingness to sign a written informed consent document.
12. Stage Two: The participant has a histologically confirmed index lesion that is either: An EARLY premalignant lesion defined to be at high risk as indicated by the presence of at least one of the following: atypical cells, mild dysplasia, or hyperplastic leukoplakia of high-risk sites, dorsal, lateral or ventral tongue and floor of mouth OR An ADVANCED premalignant lesion defined as the presence of at least one of the following: moderate dysplasia, severe dysplasia (excluding carcinoma in situ) or erythroplakia*.
13. continuation of Inclusion 12.) Stage Two: * Due to the high risk for progression associated with erythroplakia, erythroplakia of any histology will be defined as an ADVANCED oral premalignant lesion
14. The participant meets the following laboratory eligibility criteria during a time not to exceed 4 weeks prior to randomization: Hemoglobin levels equal to or above the lower limit of normal, White blood cells >/= 3,000/microL, Platelets >/= 125,000/microL, Total bilirubin </= 1.5 x ULN, AST (SGOT)/ALT (SGPT) </= 1.5 x ULN, BUN and serum creatinine </= 1.5 x ULN
15. Refer to Inclusion 9.) & 10.) If the participant is female and of childbearing potential she has a documented negative serum pregnancy test within 14 days prior to randomization.
16. The participant has a baseline EKG that does not show signs of acute cardiac ischemia or cardiac dysrhythmia (except for 1st degree AV block or chronic atrial fibrillation). EKG can be an earlier report within 12 weeks prior to registration.
17. Both men and women and members of all races and ethnic groups are eligible for this trial. The investigators will strive to recruit subjects of a demographic that reflect those affected with oral premalignant lesions in the general population. Cancer statistics show that the prevalence of oral precancer and oral cancer is higher among males than females, at a ratio of 1.3:1. All consenting investigators and professionals will be informed of the importance of recruiting women to the current trial. This effort will ensure that we have adequate representation of women.
18. Continuation of Inclusion 17.) Similarly, our investigators are extremely aware of the importance of recruiting minority. In summary, a specific effort will be made to recruit and retain woman and minorities to the current trial. It is anticipated that 40% of the subjects enrolled to the current trial will be female, and that approximately 12% of the study population will be Hispanic or Latino.

Exclusion Criteria:

1. The participant has active cancer or carcinoma in situ of the head and neck.
2. The participant has a contraindication to biopsy.
3. The participant has presence of congestive heart failure (New York Heart Association (NYHA) Class II-IV), uncontrolled hypertension (systolic >150 or diastolic >100), or unstable angina.
4. The participant has any history of congestive heart failure or history of myocardial infarction within the past 6 months.
5. The participant exhibits clinical evidence of active liver disease or history of chronic liver disease.
6. The participant has > CTCAE Grade 1 edema.
7. The participant has known diabetes and is on insulin or oral agents. The participant is receiving medical therapy for dysregulated blood sugar. The participant has a random blood glucose level >200 mg/dl.
8. The participant currently receives an enzyme inhibitor of CYP2C8 (such as gemfibrozil), or enzyme inducer (such as rifampin).
9. The participant has experienced jaundice with Rezulin® (troglitazone).
10. The participant has a history of colorectal cancer, familial adenomatous polyposis (FAP) or hereditary non-polyposis colorectal cancer (HNPCC).
11. The participant has a history of bladder cancer or in situ bladder cancer.
12. The participant has a history of invasive cancer within the past 18 months (excluding nonmelanoma skin cancer and in situ cervical cancer). Participants (excluding those with a history of colorectal cancer, FAP, HNPCC, bladder cancer or in situ bladder cancer) who received curative treatment and have shown no evidence of recurrence for 18 months will be eligible.
13. The participant has had chemotherapy, cancer-related immunotherapy, hormonal therapy (other than HRT for menopause), or radiation therapy within 18 months of the Baseline visit.
14. The participant will need concurrent chemotherapy, radiotherapy, hormonal (other than HRT for menopause), or cancer-related immunotherapy during the time of study.
15. The participant has received any investigational medication within 30 days of the Baseline visit or is scheduled to receive an investigational drug during the course of the study.
16. The participant has participated in the study previously and was withdrawn.
17. The participant is pregnant or nursing.
18. Participants who have received pioglitazone or rosiglitazone prior to this study.
19. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, HIV, or psychiatric illness/social situations that would limit compliance with study requirements. Medical and scientific reasons for the exclusion of pregnant or nursing participants or participants who are HIV-positive from this study are detailed below. Pregnant women are excluded from this study because pioglitazone is an agent with the potential for teratogenic or abortifacient effects.
20. Continuation of Exclusion 19.) Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pioglitazone, breastfeeding should be discontinued if the mother is treated with pioglitazone.
21. Continuation of Exclusion 20.) HIV-positive: Known HIV-positive participants will be excluded from this study due to the high prevalence of confounding oral lesions in this population. Specifically, HIV infection is a risk factor for developing Epstein-Barr virus related abnormalities including Greenspan's leukoplakia or oral hairy leukoplakia. In addition, HIV-positive patients are susceptible to candidiasis which can cause white patches of the mouth.