Background. Cryptococcal meningitis (CM) is the proximate cause of death in 20%–30% of persons with acquired immunodeficiency syndrome in Africa. Methods. Two prospective, observational cohorts enrolled human immunodeficiency virus (HIV)—infected, antiretroviral-naive persons with CM in Kampala, Uganda. The first cohort was enrolled in 2001–2002 (n=92), prior to the availability of highly active antiretroviral therapy (HAART), and the second was enrolled in 2006–2007 (n=44), when HAART was available. Results. Ugandans presented with prolonged CM symptoms (median duration, 14 days; interquartile range, 7–21 days). The 14-day survival rates were 49% in 2001–2002 and 80% in 2006 (P<.001). HAART was started 35±13 days after CM diagnosis and does not explain the improved 14-day survival rate in 2006. In 2006–2007, the survival rate continued to decrease after hospitalization, with only 55% surviving to initiate HAART as an outpatient. Probable cryptococcal-related immune reconstitution inflammatory syndrome occurred in 42% of patients, with 4 deaths. At 6 months after CM diagnosis, 18 persons (41%) were alive and receiving HAART in 2007. The median cerebral spinal fluid (CSF) opening pressure was 330 mm H2O; 81% of patients had elevated pressure (>200 mm H2O). Only 5 patients consented to therapeutic lumbar puncture. There was a trend for higher mortality for pressures >250 mm H2O (odds ratio OR, 2.1; 95% confidence interval CI, 0.9–5.2; P=.09). Initial CSF WBC counts of <5 cells/mL were associated with failure of CSF sterilization (OR, 17.3; 95% CI, 3.1–94.3; P<.001), and protein levels <35 mg/dL were associated with higher mortality (OR, 2.0; 95% CI, 1.2–3.3; P=.007). Conclusions. Significant CM-associated mortality persists, despite the administration of amphotericin B and HIV therapy, because of the high mortality rate before receipt of HAART and because of immune reconstitution inflammatory syndrome—related complications after HAART initiation. Approaches to increase acceptance of therapeutic lumbar punctures are needed.