CD4⁺ T cells play a central role in the immunopathogenesis of HIV/AIDS, and their depletion during chronic HIV infection is a hallmark of disease progression. However, the relative contribution of CD4⁺ T cells as mediators of antiviral immune responses and targets for virus replication is still unclear. Here, we have generated data in SIV-infected rhesus macaques (RMs) that suggest that CD4⁺ T cells are essential in establishing control of virus replication during acute infection. To directly assess the role of CD4⁺ T cells during primary SIV infection, we in vivo depleted these cells from RMs prior to infecting the primates with a pathogenic strain of SIV. Compared with undepleted animals, CD4⁺ lymphocyte–depleted RMs showed a similar peak of viremia, but did not manifest any post-peak decline of virus replication despite CD8⁺ T cell– and B cell–mediated SIV-specific immune responses comparable to those observed in control animals. Interestingly, depleted animals displayed rapid disease progression, which was associated with increased virus replication in non-T cells as well as the emergence of CD4-independent SIV-envelopes. Our results suggest that the antiviral CD4⁺ T cell response may play an important role in limiting SIV replication, which has implications for the design of HIV vaccines.