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In this prospective study, we assessed the simplified multi-organ dysfunction score (sMODS) in 485 consecutive African children, hospitalized with Plasmodium falciparum malaria. Children were grouped according to their ability to walk unaided (Group 1, N = 414), sit unaided (Group 2, N = 63), or inability of both (Group 3, N = 8) before contracting malaria. The sMODS on admission to hospital was highly correlated with prolonged disease duration in Groups 1 and 2 (Spearman r = 0.79 and r = 0.78, respectively). A sMODS of ≥ 16 was indicative for prolonged disease duration in Group 1 (> 48 hours of inability to walk, sensitivity of 87%, specificity of 82%) and Group 2 (> 24 hours of inability to sit, sensitivity of 100%, and specificity of 78%.). The simplified MODS is a simple and sensitive measure merit of severity of illness in children with P. falciparum malaria and allows early prognostic evaluation.