Patients present with headache, personality changes, irritability, somnolence, and cognitive changes. Intracranial pressure may be increased. There may be cranial nerve deficits. The diagnosis can only be made definitively by lumbar puncture, which typically shows an increased opening pressure, a mononuclear pleocytosis, an elevated protein concentration, and reduced glucose level in the cerebrospinal fluid (CSF). India ink preparations can define the yeast, but this is now rarely performed; cultural isolation is preferred but may take several days. Measurement of cryptococcal capsular antigen in the CSF is helpful in suggesting cryptococcal infection while the cultures are still pending. The clinical context generally requires that the brain is imaged before lumbar puncture to exclude space-occupying lesions; when present, these are typically the result of other disorders, such as lymphoma.

A fatal outcome is likely in the absence of treatment, which generally involves intravenous amphotericin B and oral flucytosine for at least 2 weeks, followed by high-dose fluconazole therapy for 2 months. Maintenance lower-dose therapy with fluconazole is then continued for at least a year, when discontinuation can be considered, depending on the response to antiretroviral therapy.

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