Abstract Background Increased intracranial pressure (ICP) frequently complicates cryptococcal meningitis. Therapeutic lumbar punctures (LPs) have acute survival benefits in the first week, and we sought to understand the longer-term survival impact of therapeutic LPs. Methods We prospectively enrolled human immunodeficiency virus (HIV)–seropositive adults with cryptococcal meningitis from 2013 to 2017 in Uganda. We assessed the association between clinical characteristics, CSF parameters, and 14- and 30-day mortality by baseline ICP. We also assessed 30-day mortality by number of follow-up therapeutic LPs performed within 7 days. Results Our analysis included 533 participants. Participants with baseline ICP >350 mm H2O were more likely to have Glasgow Coma Scale (GCS) score <15 (P < .001), seizures (P < .01), and higher quantitative cryptococcal cultures (P < .001), whereas participants with ICP <200 mm H2O were more likely to have baseline sterile CSF cultures (P < .001) and CSF white blood cell count ≥5 cells/µL (P = .02). Thirty-day mortality was higher in participants with baseline ICP >350 mm H2O and ICP <200 mm H2O as compared with baseline ICP 200–350 mm H2O (hazard ratio, 1.55 [95% confidence interval, 1.10–2.19]; P = .02). Among survivors at least 7 days, the 30-day relative mortality was 50% higher among participants who did not receive any additional therapeutic LPs compared to those with ≥1 additional follow-up LP (33% vs 22%; P = .04), irrespective of baseline ICP. Conclusions Management of increased ICP remains crucial in improving clinical outcomes in cryptococcal meningitis. Guidelines should consider an approach to therapeutic LPs that is not dictated by baseline ICP.