Severe malaria is characterized by a massive release of proinflammatory cytokines in the context of sequestration of parasitized and normal red cells (RBCs). High-mobility group box 1 (HMGB1) is a DNA- and heparin-binding protein that also acts as a cytokine when released from cells in the extracellular milieu after a proinflammatory stimulus. In this study, we have measured the circulating levels of HMGB1 in 76 children with severe or uncomplicated malaria. Sera from both severe (P = 0.0022) and uncomplicated (P = 0.0049) patients had significantly higher circulating HMGB1 levels compared with healthy controls. Elevated HMGB1 in patients with ongoing Plasmodium falciparum infections might prolong inflammation and the febrile state of malaria and could offer a potential target for therapeutic intervention.