The mechanisms by which HIV induces immunosuppression are still poorly understood so far. Several pathways of CD4 cell destruction are known, including cytolysis with or without syncitium formation and killing by cytotoxic effectors of HIV infected or non-infected CD4 cells. However, a discrepancy exists between the small number of actually infected cells in vivo and the extent of HIV-related immunodeficiency. Among other possible immunosuppressive factors, serum blocking factors have been reported, but only in AIDS-related opportunistic infections (OI), i.e. in a quite specific type of full-blown HIV disease. The purpose of this work was to determine whether serum blocking activity was unique to this group of patients, or if it was also expressed in other clinical presentations and, moreover, at earlier stages of the disease. We also attempted to delineate the nature of these seric factors. In order to do so, we assessed serum suppressive activity of 50 HIV seropositive patients, seven with OI, eight with Kaposi's sarcoma (KS), and 35 with no clinical AIDS. Our results confirm the existence of serum inhibiting factors in AIDS, and demonstrate their presence at earlier stages of the disease. They also highlight the fact that the level of serum suppression does not correlate with patients clinical status, but increases with the severity of the disease. The lower the CD4 count, the higher the suppression exerted. Furthermore, we showed that the suppression was at least partly mediated by small size molecules, which are not complement-mediated or directly lymphocytotoxic. On the other hand, this activity does not correlate with the serum level of p24 HIV core protein. The possible relation with other viral components is discussed. The relevance of these data to prognosis and pathogenesis of HIV disease deserves further investigation.