To investigate the role of tumor necrosis factor in Plasmodium falciparum infections, we measured serum concentrations of this cytokine in 65 Malawian children with severe falciparum malaria. Of these children (mean age, 5.3 years), 55 were unconscious and 10 had hypoglycemia at presentation. Although there was considerable overlap, the mean (+/- SEM) initial serum concentration of tumor necrosis factor was significantly higher in the 10 patients who died (709 +/- 312 pg per milliliter) than in the 55 who survived (184 +/- 32 pg per milliliter; P less than 0.02). The mortality rate increased with the concentration of tumor necrosis factor: at a level of less than 100 pg per milliliter, 1 of 24 patients died; at 100 to 500 pg per milliliter, 6 of 34 patients; and at more than 500 pg per milliliter, 3 of 7 patients. High concentrations of tumor necrosis factor were also associated with hypoglycemia (P less than 0.02), hyperparasitemia (P less than 0.002), age under three years (P less than 0.03), and severity of illness as measured by a prognostic index (P less than 0.0005). The highest serum concentrations of tumor necrosis factor were found in patients who died shortly after admission. The concentrations in cerebrospinal fluid were within the normal range in all patients. In serum samples obtained from 38 convalescent patients, the concentration of tumor necrosis factor declined to a mean of 16 +/- 3 pg per milliliter. We conclude that the level of tumor necrosis factor is frequently increased in patients with severe falciparum malaria, particularly in those with cerebral malaria or hypoglycemia. To determine whether it is important in the pathogenesis of the signs and symptoms of the disease requires further study.