To investigate the relationship of TNFα levels to Plasmodium falciparum (PF) infection, plasma TNFα concentrations were measured in Pakistani adults and children with mild, severe, cerebral and chronic falciparum malaria and healthy (control) subjects. The initial geometric mean plasma concentrations of TNFα in adult patients with severe malaria (187.6 pg/mL) were significantly higher than mild malaria patients (87.1 pg/mL, P < 0.001). TNFα levels were not correlated to parasite density, cerebral malaria, young age, hypoglycemia or fatal outcome; however, they were associated with severe anemia, and hepatic and kidney dysfunction. TNFα levels were not significantly increased in 16 patients with hyperparasitemia and were significantly elevated (P < 0.02) in chronic malaria patients as compared to control subjects. TNFα levels were elevated independently in patients with anemia, hypoglycemia (P < 0.001, P < 0.05), and hepatic and kidney (P < 0.001 each) dysfunction. In this study, high TNFα levels were associated with several manifestations of severe malaria and were not specific to cerebral malaria and hyperparasitemia.