Objective To validate surrogate endpoints for mortality in intervention studies in patients with severe malaria Design Retrospective evaluation of large intervention studies in severe malaria Setting, Patients Three datasets were used: clinical studies in adult patients from Bangladesh, African children enrolled in the ‘AQUAMAT’ study comparing artesunate and quinine, and adult Vietnamese patients in the ‘AQ’ study comparing artemether with quinine. Measurements Sequential measurements of plasma lactate and coma score, assessed as absolute change, relative change, slope of the log coma score/lactate time curve and time to clearance/recovery. The prognostic significance of these dynamic measures for mortality were assessed as well as the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Main results Improvements in lactate levels or coma scores, as assessed by any of the explored methods over the first 24 hours of admission, were strongly prognostic for survival in all data sets. The lower adjusted mortality with artemether compared to quinine closely correlated with faster lactate clearance; in hyperlactataemic patient in the AQ study (n=173), the PTE of the relative change in plasma lactate at 8 and 12 hours was 0.81 and 0.75, respectively, indicating good performance. In paediatric patients enrolled in the ‘AQUAMAT’ study with cerebral malaria (n=829), treatment with artesunate as opposed to quinine improved survival, but was not associated with faster coma recovery, whatever measure of improvement was used. Conclusion The relative changes in plasma lactate assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality.