Disturbances in inflammatory cytokine production and immune regulation coupled with human herpesvirus-8 (HHV-8) infection underlie the current understanding of the pathogenesis of Kaposi's sarcoma (KS), the most common HIV-associated malignancy. The low affinity Fc gamma receptors (FcgammaR) for IgG link humoral and cellular immunity by mediating interaction between antibodies and effector cells, such as phagocytes and natural killer cells. We examined the frequency of polymorphic forms of the low affinity FcgammaRs, FcgammaRIIA, FcgammaRIIIA, and FcgammaRIIIB in 2 cohorts of HIV-infected men with KS and found that the FcgammaRIIIA genotype exerts a significant influence on susceptibility to or protection from KS. The FF genotype was underrepresented in patients with KS, whereas the VF genotype was associated with development of KS. A similar association was observed between FcgammaRIIIA genotypes and HHV-8 seropositivity. These observations suggest a possible role for FcgammaRIIIA in the development of KS during HIV infection.