CD4+ T lymphocyte subsets are targeted to different degrees by SIV infection. We studied central memory, effector memory, naïve, and regulatory T cell levels longitudinally in 11 SIV(mac251)-infected pigtail macaques. Depletion of CD28+CD95+ central memory CD4+ T cells, but not other populations, correlated with both SIV viral load and disease progression. A low pre-infection level of central memory CD4+ T cells was also predictive of rapid disease progression. If confirmed in larger studies, our results suggest stratifying macaques for baseline central memory CD4+ T cells would be useful in defining both the pathogenesis of SIV disease and SIV vaccine efficacy.