We show that proteome-patterns from both crude and prefractionated plasma samples accurately define childhood malaria syndromes in the discovery cohort. We confirmed these findings using a prospectively collected validation cohort. Malaria infection introduces distinguishable changes in the plasma proteome of children as seen by the striking differences between the malarianegative CC and the malaria-positive children groups. The plasma proteome differences are specific for the malaria disease process and not surrogate markers of acute illness, as we are able to accurately distinguish between malaria-negative ill children and malaria-positive groups independently of their disease severity. We have also discovered plasma proteome differences that are specific to each of the childhood malaria syndromes assessed in the present study. Our findings provide a starting point to refine the current WHO definitions of these syndromes, which lack the necessary specificity to further study severe malaria pathogenesis.