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We summarize current information on Fc receptor-mediated antiviral activities of antibodies. These activities include Fcγ receptor-mediated inhibition and neutralization of HIV on antigen-presenting cells, antibody-dependent cellular cytotoxicity, and antibody-dependent cell-mediated virus inhibition (ADCVI).An Fcγ receptor-mediated mechanism that results in augmented neutralization and may render nonneutralizing antibodies inhibitory has been demonstrated in antigen-presenting cell. Antibody-dependent cellular cytotoxicity antibody activity correlates inversely with HIV disease progression in humans, and higher vaccine-induced antibody-dependent cellular cytotoxicity antibody responses are associated with lower acute simian immunodeficiency virus viremia levels in macaques. Following vaccination with rgp120, ADCVI antibody levels are higher among those with a lower rate of sexually acquired HIV infection. Nonneutralizing simian immunodeficiency virus immune serum that prevents infection of newborn macaques after oral challenge has potent ADCVI antibody activity. Abrogating the ability of the Fc segment of the broadly neutralizing mAb b12 to bind to Fcγ receptors and to mediate ADCVI substantially reduces b12's protective effect in a simian/human immunodeficiency virus vaginal challenge model.Fc–FcγR interactions play a critical role in the biological function of antibody and are likely to be instrumental in preventing or modulating lentiviral infection. Exploiting antibody responses that depend on Fc–FcγR interactions may help widen the breadth and increase the potency of vaccine-induced antibody. Although the importance of generating optimal Fab–antigen interactions cannot be overestimated, improving Fc–FcγR interactions through adjuvants or other strategies provides another option for improving HIV vaccines and immunotherapies.