Antiphospholipid antibodies (aPL) and free protein S (PSF) deficiency have been associated with clinical thrombosis. Previous reports described a high prevalence of these abnormalities in HIV-infected individuals, but suggested there was little associated clinical thrombosis. A cohort of 74 HIV-infected men were studied for aPL, PSF deficiency and the development of thrombosis. aPL, predominantly anticardiolipin antibodies (aCL), were detected in 86% and PSF deficiency in 33%. While 42% of men with aPL also had low PSF levels, there was no correlation between aCL titres or most measures of aPL and PSF levels. However, a strong correlation was noted between a subset of aPL that reacted to phosphatidylethanolamine by hexagonal array assay and low PSF levels. There was no significant correlation between aPL, PSF deficiency and clinical features (medication use, opportunistic infection, CD4 cell count) of HIV in 60 patients for whom clinical information was available. The overall incidence of thrombosis in this group was 18%, and thrombosis developed in 6.6% of those followed prospectively over a median follow-up of 12 months. Development of thrombosis was not significantly correlated with aPL or PSF deficiency, but the high prevalence of these abnormalities may necessitate larger study groups to determine the risk associated with these coagulation changes. Study of a larger group with careful analysis of subsets of aPL, especially those associated with low PSF levels, and longer clinical follow-up could identify the HIV-infected individuals at risk for thrombosis.