Inclusion Criteria - Step 1

• Cryptococcal meningitis documented either by a positive CSF cryptococcal culture, a positive CSF India ink preparation, or a positive CSF cryptococcal antigen latex agglutination test within 7 days prior to entry
• CSF collection for quantitative cryptococcal culture within 72 hours prior to study entry or planned to be performed at study entry
• HIV-1 infection documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load
• Ability to take oral medications.
• For patients with a co-morbid complication of HIV, including opportunistic infections, receipt of stable treatment for the co-morbid complication and clinically stable, as judged by the site investigator
• For female participants of reproductive potential a negative serum or urine pregnancy test result must be obtained within 2 days prior to study entry
• All participants must agree not to participate in the conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization).
• If participating in sexual activity that could lead to pregnancy, all participants must use two forms of contraception while on study treatment and for 6 weeks after fluconazole (at any dose greater than a single 150 mg dose) has been discontinued. More information on this criterion can be found in the protocol.
• Participants who are not of reproductive potential are eligible without the requirement to use contraception. More information on this criterion can be found in the protocol.
• Willingness and ability to adhere to dose schedules and mandatory procedures
• Measured or calculated creatinine clearance of 50 mL/min or more within 3 days prior to study entry
• Required laboratory values within 3 days prior to study entry. More information on this criterion can be found in the study protocol
• Ability and willingness of the participant or legal guardian/representative to give informed consent
• Availability at the site of at least 2 weeks of its standard of care ampho B-based regimen

Exclusion Criteria - Step 1

• Expected survival of 2 weeks or less, in the opinion of the site investigator
• For patients with a co-morbid complication of HIV, anticipated difficulty, in the opinion of the site investigator, in judging response to study treatment as a result of the co-morbid complication or the drugs used to treat it
• A prior episode of CM, either as indicated by patient or as noted in patient medical records
• Use of certain drugs, within specified time periods. More information on this criterion can be found in the study protocol.
• Suspected or active tuberculosis (TB), even if untreated, for participants screening at the time that a 1200 mg daily fluconazole induction cohort is enrolling
• Known allergy, sensitivity to, or intolerance of fluconazole or other imidazole or triazole compounds, or to ampho B or other components of the standard of care ampho-B based regimen
• History of clinically significant cardiac disease, in opinion of site investigator, including symptoms of ischemia, coronary artery disease, congestive heart failure, or arrhythmia
• ECG (electrocardiogram) with QTc interval greater than 450 msec within 7 days prior to study entry.
• History of CNS disorder (excluding mood disorders) or concurrent CNS disorder(s) that, in the opinion of the investigator, would interfere with assessment of efficacy (e.g., ability to perform CSF sampling) such as lymphoma, neurocysticercosis, or toxoplasmosis
• Receipt of investigational drug therapy within 30 days prior to study entry without prior approval
• Receipt of specified treatments for the current episode of CM. More information on this criterion can be found in the study protocol.
• Active drug or alcohol use, dependence, or other conditions that in the opinion of the site investigator would jeopardize the safety of a participant in the study or would render the person unable to comply with the study plan
• Breast-feeding

Inclusion Criterion - Step 2

• Randomization to an ampho B-based regimen in Step 1
• Receipt of at least one dose of ampho B-based regimen in Step 1
• Premature discontinuation of ampho B in response to the occurrence of any treatment-limiting toxicity, as described in section 5 of the A5225/HiFLAC MOPS

Exclusion Criterion - Step 2

• Receipt of fluconazole monotherapy in Step 1
• Receipt of 8.4 mg/kg or more of ampho B
• At or beyond Day 17 in Step 1.

Inclusion Criteria - Step 3

• For participants in Step 1 who are currently receiving study-provided fluconazole, a negative CSF culture after 2 weeks incubation from a sample obtained at or before week 6 (day 35-49)
• For participants in Step 1 who are currently receiving an ampho B-based regimen or alternative treatment, completion of approximately 2 weeks of treatment
• For participants in Step 2 who are currently receiving study-provided fluconazole, negative CSF culture after 2 weeks incubation from a sample obtained at or before week 6 (day 35-49).

Exclusion Criteria - Step 3

• On study treatment beyond week 10 (day 77) in Step 1 or Step 2

Inclusion Criteria - Step 4

• On study treatment at week 10 (day 63-77)

Exclusion Criteria - Step 4

• None