The early immune response fails to prevent the establishment of chronic human immunodeficiency virus (HIV) infection but may influence viremia during primary infection, thereby possibly affecting long-term disease progression. CD25(+) FoxP3(+) regulatory T cells may contribute to HIV/simian immunodeficiency virus (SIV) pathogenesis by suppressing efficient antiviral responses during primary infection, favoring high levels of viral replication and the establishment of chronic infection. In contrast, they may decrease immune activation during chronic infection. CD4(+) regulatory T cells have been studied in the most detail, but CD8(+) CD25(+) FoxP3(+) T cells also have regulatory properties. We monitored the dynamics of CD25(+) FoxP3(+) T cells during primary and chronic SIVmac251 infection in cynomolgus macaques. The number of peripheral CD4(+) CD25(+) FoxP3(+) T cells paralleled that of memory CD4(+) T cells, with a rapid decline during primary infection followed by a rebound to levels just below baseline and gradual depletion during the course of infection. No change in the proportion of CD25(+) FoxP3(+) T cells was observed in peripheral lymph nodes. A small number of CD4(+) CD25(+) FoxP3(+) T cells at set point was associated with a high plasma viral load. In contrast, peripheral CD8(+) CD25(+) FoxP3(+) T cells were induced a few days after peak plasma viral load during primary infection. The number of these cells was positively correlated with viral load and negatively correlated with CD4(+) T-cell activation, SIV antigen-specific proliferative responses during primary infection, and plasma viral load at set point, with large numbers of CD8(+) CD25(+) FoxP3(+) T cells being indicative of a poor prognosis.