We examined the effect of viremia on cell contact and soluble factor–mediated suppression of endogenous human immunodeficiency virus (HIV) replication in CD4⁺ T cells from HIV-1–infected individuals by autologous natural killer (NK) and CD8⁺ T cells. NK cells suppressed HIV replication as effectively as did CD8⁺ T cells. Suppression of HIV replication by NK cell culture supernatant was predominantly mediated by CC-chemokine secretion and was considerably greater in patients without viremia than in patients with viremia. Furthermore, there was an inverse correlation between the level of viremia and the ability of NK cells and NK-derived supernatants to suppress virus replication. The ability of NK cells to control HIV replication was independent of levels of interferon-γ expression and cytolytic activity. Our results demonstrate that NK-mediated suppression of HIV replication is as potent as that of CD8⁺ T cells; it is mediated predominantly by secretion of CC-chemokines, and the presence of viremia markedly impairs this NK-mediated inhibitory effect on HIV replication