Background Cryptococcal meningitis (CCM) is the leading cause of meningitis in people living with HIV (PLWH) in sub-Saharan Africa (SSA). The mortality and morbidity associated with CCM remain high. Combination of antifungal therapy, diligent management of intracranial pressure (IP) and the correct timing of the introduction of antiretroviral therapy (ART) minimise the risk of mortality and morbidity. The absence of spinal manometers in many healthcare centres in SSA challenges the accurate measurement of cerebrospinal fluid (CSF) pressure and its control. Objectives We hypothesised that four lumbar punctures (LPs) in the first week of the diagnosis and treatment of CCM would reduce IP such that in-hospital mortality and morbidity of HIV-associated CCM (HIV/CCM) would be significantly reduced. Methods We conducted a retrospective study to assess whether receipt of four or more LPs in the first week of the diagnosis and treatment with combination antifungal therapy of HIV/CCM would be associated with the reduction of in-hospital mortality in adult PLWH. Results From 01 January 2016 to 31 December 2016, 116 adult patients were admitted to the Dora Nginza District Hospital in Zwide, Port Elizabeth, South Africa. After exclusion of 11 (two were younger than 18 years, two had missing hospital records and seven demised or left the hospital before 7 days of hospitalisation), 105 patients were included in the analysis. The mean age was 39.4 (standard deviation [s.d.] ± 9.7) years, 64.8% were male. All were PLWH. A total of 52.4% had defaulted ART and 25.7% were ART naïve. Forty-three patients received four or more LPs (mean = 4.58 [± 0.96]) in the first week of hospitalisation with an associated in-hospital mortality of 11.6% ( n = 5/43) compared with 62 patients who received less than four LPs (mean = 2.18 [± 0.80]) with an in-hospital mortality of 29% ( n = 18/62) and a relative risk of 0.80 (95% CI, 0.66–0.97), p = 0.034. Conclusion In the current study of adult PLWH presenting to hospital with HIV/CCM, four or more LPs in the first 7 days following admission and the initiation of treatment were associated with a 17.4% reduction in absolute risk of in-hospital mortality and a 20% reduction in relative risk of in-hospital mortality. This mortality difference was noted in patients who survived and were in hospital at the time of the 7-day study census and persisted until the time of hospital discharge.