Two EIAs (Medgenix and Quantikine) and a bioassay were used to measure tumor necrosis factor-alpha (TNF alpha) in serum samples from 73 human immunodeficiency virus type 1 (HIV-1)-seropositive patients and in samples from 2 control groups. All clinical groups of HIV-1-infected patients, regardless of concurrent illness, had significantly elevated levels of both types of soluble TNF receptors (sTNFRs) and immunoreactive TNF alpha (Medgenix EIA), with the highest concentrations among the AIDS patients. These TNF parameters were significantly correlated with reduced CD4+ lymphocyte counts. Only a few HIV-1-infected patients had detectable TNF alpha levels measured by the Quantikine EIA. TNF alpha bioactivity was significantly raised only in the AIDS group. Serially measured sTNFRs, expressed as sTNFR slopes, were significantly associated with survival in the patient group. The raised levels of immunoreactive TNF alpha and sTNFRs strongly indicate activation of the TNF alpha system during HIV-1 infection. Levels increase with disease progression and degree of immunodeficiency; thus, serially measured sTNFRs may give useful prognostic information in HIV-1 infection.