The contribution of natural killer (NK) cells to the immune containment of human immunodeficiency virus infection remains undefined. To directly assess the role of NK cells in an AIDS animal model, we depleted rhesus monkeys of >88% of CD3⁻ CD16⁺ CD159a⁺ NK cells at the time of primary simian immunodeficiency virus (SIV) infection by using anti-CD16 antibody. During the first 11 days following SIV inoculation, when NK cell depletion was most profound, a trend toward higher levels of SIV replication was noted in NK cell-depleted monkeys compared to those in control monkeys. However, this treatment did not result in significant changes in the overall levels or kinetics of plasma viral RNA or affect the SIV-induced central memory CD4⁺ T-lymphocyte loss. These findings are consistent with a limited role for cytotoxic CD16⁺ NK cells in the control of primary SIV viremia.