Hypoglycaemia is an important complication in severe malaria, ascribed to an inhibition of gluconeogenesis. However, the only data available suggested that in severe malaria, total glucose production is increased. We measured glucose production and gluconeogenesis after an overnight fast in all seven patients with cerebral malaria (CM) consecutively admitted to Bao Loc General hospital over a 2-year period, and in six healthy sex- and age-matched controls. Glucose production was measured by infusion of [6,6-(2)H(2)]glucose and the contribution of gluconeogenesis by oral ingestion of (2)H(2)O. Compared to controls, plasma glucose concentration was 42% higher in CM patients (p=0.004), and glucose production was doubled (p=0.003). Gluconeogenesis contributed 100% of the total glucose in CM patients but only 58% in controls (p=0.003). The plasma concentrations of the substrates for gluconeogenesis and the glucoregulatory hormones were not different between patients and controls, except for an increase in lactate and cortisol in the patients. Cerebral malaria is associated with increases rather than decreases in plasma glucose, glucose production and gluconeogenesis, and there is no contribution of glycogenolysis to glucose production. Factors other than malaria per se are involved in the pathogenesis of hypoglycaemia associated with CM.