Here we report the results of an investigation into the possibility that one mechanism responsible for the establishment of persistent human immunodeficiency virus infection is an early regulatory T (T_reg) cell response that blunts virus-specific responses. Using the simian immunodeficiency virus (SIV)–infected rhesus macaque model, we show that, indeed, viral replication and immune activation in lymphatic tissue drive a premature immunosuppressive response, with dramatic increases in the frequencies of CD4⁺CD25⁺FOXP3⁺ T_reg cells, transforming growth factor–β1⁺ cells, interleukin–10⁺ cells, and indoleamine 2,3-dioxygenase⁺CD3⁺ cells. When we compared SIV infection with rhesus cytomegalovirus (RhCMV) infection, we found that the frequency of T_reg cells paralleled the magnitude of immune activation during both infections but that the magnitude of immune activation and of the T_reg cell response were lower and peaked much later during RhCMV infection. Importantly, the frequency of T_reg cells inversely correlated with the magnitude of the SIV-specific cytotoxic T lymphocyte response. We conclude that an early T_reg cell response during acute SIV infection may contribute to viral persistence by prematurely limiting the antiviral immune response before infection is cleared