It has recently been reported that a large proportion of patients with HIV infection have low free protein S levels. In this study we show that protein S (PS) activity levels, as well as PS antigen (Ag), were significantly lower in 35 HIV-1 infected patients than in the control population (p < 0.001). When we divided HIV infected patients into three groups according to their CD4+ counts, we found that PS levels were significantly lower in patients with < 100 CD4+ cells/ul. In order to investigate the possible role of (auto)immune response in the pathogenesis of PS deficiency, the presence of anticardiolipin antibodies (aCL) and/or of the specific antibodies to protein S was evaluated. A high prevalence (77.1%) of aCL in both symptomatic and asymptomatic subjects was observed. The screening for specific anti-PS antibodies, performed by immunoblotting, showed an overall positivity of 28.6% in anti-HIV+ patients, with a higher prevalence in symptomatic than in asymptomatic patients. Interestingly, the prevalence of the positivity for anti-PS antibodies was found to be higher in anti-HIV+ patients with PS levels < 50%. Taken collectively, our findings suggest that at least one of the mechanisms through which PS levels are decreased in HIV infection, is due to the presence of specific autoantibodies.