Serum concentrations of soluble receptors for tumor necrosis factor-alpha (sTNF alpha R) types I and II, beta 2-microglobulin, and CD4 cell counts were determined at entry and 3-5 months before AIDS diagnosis in 20 untreated, asymptomatic human immunodeficiency virus type 1 (HIV-1)-seropositive subjects, who progressed to AIDS within 5.5 years of study entry, and in an equal number of HIV-seronegative and untreated seropositive controls, who remained asymptomatic. At entry, concentrations of sTNF alpha R type II and beta 2-microglobulin were elevated and increased further in progressors. The odds ratio (OR) for sTNF alpha R type II concentrations > or = 6.5 ng/mL was 18.4 and for beta 2-microglobulin concentrations > or = 3 mg/L was 6.6; CD4 cell counts were not predictive. Five months before diagnosis, the OR was 102.0 for sTNF alpha R type II concentrations > or = 7.5 ng/mL, 13.5 for beta 2-microglobulin concentrations > or = 4 mg/L, and 6.9 for CD4 cell counts < 250/mm3 (counts < 500/mm3 were not predictive). Of the three variables, sTNF alpha R type II was proved by bivariate analysis to be the strongest and earliest predictor of disease progression.