Metabolic acidosis is a common complication of severe malaria caused by Plasmodium falciparum. The factors contributing to the acidosis were assessed in 62 children with severe falciparum malaria (cases) and in 29 control children who had recently recovered from mild or moderate malaria. The acidosis was largely caused by the accumulation of both lactic and 3-hydroxybutyric acids. The determinants of oxygen release to the tissues were also examined; although there was no difference between cases and controls in respect of 2,3-bisphosphoglycerate and mean corpuscular hemoglobin concentration, there was a marked increase in P50 in the cases, caused by pyrexia, low pH, and base deficit. There was substantial relative or actual hypoglycemia in many cases. The relationship of these observations to therapeutic strategy is discussed.