The importance of CD8+ T cells in the control of HIV/SIV infection has been extensively reported. However, the reason why CD8+ T cells do not sufficiently control or clear virus is unknown. Importantly, cytolytic properties of CD8+ T cells are highly correlated with control of HIV/SIV infection as demonstrated in elite controller subjects yet are poorly maintained in chronically infected subjects. In addition, reduced killing functions by lymph node CD8+ T cells as compared to blood CD8+ T cells have been described during chronic HIV infection suggesting a semi-immune privilege environment of lymph nodes. To date, the evolution of cytolytic SIV-specific CD8+ T cells in anatomical compartments associated with viral reservoir and replication has not been thoroughly evaluated. As such, we implemented the Rhesus macaque SIV infection model to characterize the evolution and tissue-distribution of cytolytic SIV-specific memory CD8+ T cells during acute infection. We found robust acute phase cytolytic potential to be short-lived, in part consequential of low levels of T-bet, in all evaluated tissues though most pronounce in secondary lymphoid tissues. In addition, we observed the lowest frequencies of effector memory differentiated SIV-specific CD8+ T cells within secondary lymphoid tissues as compared to the circulation, even during peak viremia. Moreover, secondary lymphoid tissues appear to provide an environment with reduced cytotoxic effector CD8+ T cell pressures that is favorable for viral reservoir formation and persistent viral replication in these tissues.