Forty-one African patients suffering from clinically defined severe malaria were studied in the intensive medical care unit of the main hospital in Dakar, Senegal, West Africa. All of these individuals lived in Greater Dakar, an area of low and seasonal Plasmodium falciparum endemicity. Twenty-seven patients (mean age +/- 1 standard deviation, 19.2 +/- 12.7 years) survived this life-threatening episode, but 14 (30.8 +/- 16.2 years old) died despite initiation of adequate treatment. On the day of admission (day 0) and 3 days later, one to two blood samples (i.e., approximately 10 to 15 ml) were obtained from each subject, and different biological parameters were evaluated in the two groups. Plasma samples were tested for their content in tumor necrosis factor alpha (TNF-alpha), soluble receptors I and II for TNF-alpha (TNF-alpha sRI and TNF-alpha sRII), interleukin-6 (IL-6), IL-6 sR, IL-10, and IL-2 sR. The concentrations of all these cytokines and/or their receptors was significantly elevated in patient plasma samples on day 0, and it rapidly decreased in the group of individuals who survived. By comparison, the mean concentration of the same parameters decreased slowly in the group of patients who died (except for IL-10, which dramatically fell in all patient plasma samples soon after initiation of antimalarial treatment). The TNF-alpha sRI level remained significantly elevated among the patients who died, and the highest levels of soluble TNF-alpha sRI receptor were found among the older patients. Parasite-specific immunoglobulin M (IgM), total IgG, IgG1, IgG2, IgG3, and IgG4 were evaluated by enzyme-linked immunosorbent assay using a crude extract of a local P. falciparum isolate as antigen and human class- and subclass-specific monoclonal antibodies. Parasite-specific IgM, total IgG, and IgG1 were detectable in the plasma samples of most of these African patients, whereas IgG2 and IgG4 mean values were low. The mean level of parasite-specific IgG3 was different (P = 0.024) at day 0, i.e., before initiation of intensive medical care, between the group of the 27 surviving subjects and the group of 14 patients dying of severe malaria. As a consequence, most of the African patients who died had only trace amounts or almost no detectable level of parasite-specific IgG3 at the time of admission. In contrast, the presence of even limited IgG3 activity at day 0 was found to be associated with a significantly increased probability of recovering from severe malaria. Therefore, in our study, both an elevated level of TNF-alpha sRI and absence of IgG3 activity were of bleak prognostic significance, whereas a favorable outcome was usually observed when parasite-specific IgG3 activity was detectable. This finding was strongly suggestive of a prime role for these parasite-specific immunoglobulins in the capacity to help recovery from severe malaria.