Inclusion Criteria:

1. Patients with diagnosis of refractory or relapsed AML or high-risk MDS who will receive first salvage chemotherapy. (Salvage patients are defined as patients that achieved remission and relapsed or patients who were refractory to initial frontline chemotherapy)
2. Age > 18 years and able to take oral intake.
3. Patients must sign an informed consent.
4. Patients agree to medically approved forms of contraception
5. Patients on prior antifungal prophylaxis with voriconazole, itraconazole or fluconazole are eligible if they completed 3 days wash-out period if on voriconazole, or 14 days wash-out period if on itraconazole or 7 days wash-out period if on fluconazole

Exclusion Criteria:

1. Patients with history of anaphylaxis attributed to azole compounds
2. Patients with clinical or other evidence that indicates that they have proven or probable invasive fungal infection prior to enrollment (EORTC criteria)
3. Patients with baseline total bilirubin levels > 3 times the upper normal limits (i.e. > 3.0 mg/dl); or baseline SGPT > 5 times upper limit normal.
4. Patients receiving any medication that is contraindicated with the use of posaconazole
5. Patients with baseline creatinine levels NCI grade 3 or above (> 3.0 - 6.0 X ULN)
6. Patients with baseline QTc prolongation NCI grade 1 or above (QTc > 0.45 - 0.47 seconds).
7. Patients receiving CYP3A4 substrates, such as terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine. A complete listing can be found at: ctep.cancer.gov/protocolDevelopment/docs/cyp3a4.doc
8. Patients receiving rifabutin, phenytoin, cimetidine and efavirenz, which may lower posaconazole plasma concentrations levels.