To investigate the relation of tumor necrosis factor-alpha (TNF alpha) to Plasmodium falciparum infection, plasma TNF alpha concentrations were measured in Zairian children with severe malaria, mild malaria, or other illnesses. The initial geometric mean plasma concentration of TNF alpha 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 less than .001). Among 29 parasitemic children, initial geometric mean TNF alpha levels decreased from 77 to 5 pg/ml (P less than .001) at day 7. TNF alpha 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, TNF alpha levels were elevated equally in children with cerebral malaria and with other signs of severe malaria. With multiple linear regression, TNF alpha levels were elevated independently in children with hyperparasitemia (P = .001) and severe anemia (P = .04). In this study, high TNF alpha levels were associated with several manifestations of severe malaria and were not specific to cerebral malaria.