To investigate the relation of tumor necrosis factor-α (TNFα) to Plasmodium falciparum infection, plasma TNFα concentrations were measured in Zairian children with severe malaria, mild malaria, or other illnesses. The initial geometric mean plasma concentration of TNFα among 61 children with P. falciparum infection, (71 pg/ml) was higher than the level in 26 severely ill, aparasitemic children (10 pg/ml; P < .(01). Among 29 parasitemic children, initial geometric mean TNFα levels decreased from 77 to 5 pg/ml (P < .001)at day 7. TNFα levels increased with parasite density and were associated with hyperparasitemia, severe anemia, hypoglycemia, and young age but not with cerebral malaria or fatal outcome. However, TNFα levels were elevated equally in children with cerebral malaria and with other signs of severe malaria. With multiple linear regression, TNFα levels were elevated independently in children with hyperparasitemia (P = .(01) and severe anemia (P = .04). In this study, high TNFα levels were associated with several manifestations of severe malaria and were not specific to cerebral malaria.