The objective of the study was to evaluate the role of autoimmune mechanisms in the pathophysiology of protein S deficiency during HIV-1 infection. In a prospective study the correlation between protein S activity and the presence of anti-protein S autoantibodies or anti-cardiolipin antibodies in HIV-1-positive patients and in a population of patients without HIV infection was investigated. Fifty-five HIV-1-infected patients and 15 hospitalized patients without HIV infection were analysed for protein S activity (functional assay), complement system activation, presence of autoantibodies against protein S (Dot Immunobinding) and levels of anti-cardiolipin IgG antibodies (ELISA). The presence of anti-protein S antibodies was detected in 31 (56.36%) out of the 55 HIV-1-positive patients and in three (20%) of the 15 control patients (Fisher's exact test, p = 0.012). The average value (+/- standard deviation) of protein S activity was 100.93 (14.73)% in the control group. For the HIV-1-infected patients it was 73.70 (20.67)% in those with anti-protein S antibodies compared to 88.08 (25.48)% in those without (Mann-Whitney U Test, p = 0.01). In the HIV-1-positive group protein S activity was correlated with concentrations of circulating immune complexes (Spearman rank sum test, r = -0.41, p = 0.018) and in the control group with concentrations of anti-cardiolipin antibodies (Spearman rank sum test, r = 0.709, p = 0.032). In conclusion, HIV-1 infection is associated with a high prevalence of antibodies against protein S. These antibodies are associated with a significantly low protein S activity.(ABSTRACT TRUNCATED AT 250 WORDS)