A plasma free protein S deficiency was detected in 41 of 63 patients infected with the human immunodeficiency virus type I (HIV-1). This study consisted in a prospective analysis of blood samples from 26 patients with confirmed diagnosis of AIDS, two with AIDS-related complex, 10 with polyadenopathy, and 25 who were asymptomatic. Protein S levels were compared to a matched control group of 24 healthy subjects. A deep venous thrombosis occurred in three AIDS patients with free protein S deficiency. A significant decrease in plasma free protein S levels was observed in HIV-1-seropositive patients (mean +/- SD, 56.5 +/- 23.3%) as compared with control subjects (105.3 +/- 18%, p = 0.0001). Free protein S levels were significantly lower in patients with full-blown AIDS (37.6 +/- 12.3%) than in patients without AIDS (69.8 +/- 19.9%, p = 0.0001). Low plasma free protein S levels correlated with high beta 2-microglobulin values (p = 0.0001), low CD4+ T-cell counts (p = 0.0002) and elevated urinary neopterin concentrations (p = 0.005). According to a multiple regression analysis, the progression to stages IVB, IVC1 or IVD of the Centers for Disease Control (CDC) appeared to be the main explanatory variable in free protein S-deficient patients. Such results suggest that free protein S deficiency may coincide with the development of AIDS. This could contribute to hypercoagulability and, in some instances, thromboembolic complications in AIDS patients.