Background <p>Paediatric cerebral malaria (CM) kills thousands of children globally each year. Despite multiple interventional trials, no adjunctive therapy has demonstrated a survival benefit. As CM is known to cause multiple organ dysfunction syndrome (MODS), failure to consider the immediate cause of death or cause-specific mortality may partially explain these negative findings, particularly for targeted, organ specific therapies.</p> Methods <p>A retrospective review of data from children with CM enrolled in interventional clinical trials at the Blantyre Malaria Project/Queen Elizabeth Central Hospital between 2018 and 2025 was performed. For participants who died during their hospitalization, the immediate cause of death was categorized into one of seven groups using a priori definitions.</p> Results <p>A total of 393 children were enrolled in the study period, and 52 (13%) died. Cerebral herniation was the most common immediate cause of death (46%) followed by status epilepticus with apnea (17%). Non-neurologic immediate causes of death occurred in 37% and included: cardiac failure/shock (13%), respiratory failure (12%), renal failure (6%), hepatic failure (4%), and other/indeterminant (2%). Admission coma score was significantly lower in children who died of cerebral herniation or hepatic failure (p = 0.001). Admission oxygen saturation was lowest in patients who died of respiratory failure (p = 0.04) and admission lactate was highest in those that died of cardiac failure/shock, hepatic failure, or other/indeterminant causes (p = 0.01). MODS was prevalent across the cohort regardless of the immediate cause of death.</p> Conclusions <p>Multiple different immediate causes of death were identified in children with CM. This may dilute the measured impact of brain-focused therapies aimed at reducing central nervous system injury. Modifications in sample size estimates may need to be made in future clinical trials.</p>