Background: Blood–brain barrier disruption is documented in severe falciparum malaria, but the role of the cerebrospinal fluid (CSF) proteins in pathogenesis and control of acute symptomatic seizures is not studied. We hypothesised that elevated CSF proteins (markers of blood-brain breakdown) in children admitted to the hospital with severe malaria may affect the risk for seizures in malaria and seizure control or response to anti-seizure medications (ASM). Objective: We measured CSF and plasma total protein, albumin, ferritin, and S100B concentrations in children with severe malaria to determine their associations with the risk of acute symptomatic seizures, seizure control, and response to ASM. Methods: We measured CSF levels of proteins such as albumin, ferritin, and S100B (a glial biomarker), in 45 children with carefully phenotyped seizures in the context of severe falciparum malaria admitted to hospital and documented the response of these seizures to ASM. We compared the distribution of these proteins in those with and without seizures, and in those requiring second-line ASM versus those controlled on first-line ASM. We further documented the occurrence of acute symptomatic seizures in those with evidence of blood–brain barrier disruption. Results: In the 45 children with severe falciparum malaria who had CSF protein levels measured, 36 of 45 (80.0%) had acute symptomatic seizures, of which 32 of 36 (88.9%) were complex seizures (focal, repetitive and/or prolonged). One unit increase in CSF Protein S100B levels (ng/mL) was associated with acute symptomatic seizures ((adjusted risk ratio (aRR)=1.06 (95%CI:1.01-1.11); P=0.012)). Acute symptomatic seizures, stopping spontaneously or without requiring second-line ASM, was associated with a one-unit increase in CSF ferritin levels (ng/mL) (aRR=1.12 (95%CI:1.03-1.23); P=0.008), CSF S100B levels (ng/mL) (aRR=1.33 (95%CI:1.00-1.78); P=0.051) and CSF total proteins levels (mg/L) (aRR=1.01 (95%CI:1.00-1.01); P=0.023). Seizures, responding to first-line ASM or stopping spontaneously, were more frequent in those with blood–brain barrier disruption compared to those without disruption (aRR=2.72 (95%CI:1.08-6.83); P=0.032). Evidence of blood–brain barrier disruption was associated with simple seizures. Conclusion: Elevated CSF proteins may be associated with anti-seizure activity in Kenyan children with acute symptomatic seizures admitted to hospital with severe falciparum malaria. Protein S100BB appears to be context-dependent in being involved in both the pathogenesis of acute symptomatic seizures in malaria, and in promoting a compensatory response for seizure control. Future well-powered longitudinal studies are required to confirm these findings.