Depletion of CD4(+) central memory T (TCM) cells dictates the tempo of progression to AIDS in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) both in the natural history of infection and in the context of vaccination. CD4(+) TCM cells of sooty mangabeys (SMs), a natural host for SIV in which infection is nonpathogenic, are less susceptible to SIV infection than CD4(+) TCM cells of RMs. Whether this relative protection from infection translates into increased stability of CD4(+) TCM cells in natural versus nonnatural hosts has not yet been determined. Here we compared, both cross-sectionally and longitudinally, the levels of CD4(+) TCM cells in a large cohort of SMs and RMs and the association between CD4(+) TCM levels and the main virologic and immunologic markers of disease progression. Consistent with their lower susceptibility to infection, CD4(+) TCM cells of SIV-infected SMs are lost with kinetics 20 times slower than those of SIV-infected RMs. Remarkably, the estimated length of time of SIV infection needed for CD4(+) TCM cells to fall to half of their initial levels is <16 months for RMs but >17 years for SMs. Furthermore, the fraction of proliferating CD4(+) TCM cells is significantly lower in SIV-infected SMs than in SIV-infected RMs, and the extent of CD4(+) TCM cell proliferation is associated positively with CD4(+) T cell levels in SIV-infected SMs but negatively with CD4(+) T cell levels in SIV-infected RMs. Collectively, these findings identify increased stability and maintenance of the prohomeostatic role of CD4(+) TCM cells as features distinguishing nonprogressive from progressive SIV infections and support the hypothesis of a direct mechanistic link between the loss of CD4(+) TCM cells and disease progression. OBJECTIVE Comparison of the immunologic effects of simian immunodeficiency virus (SIV) infection on rhesus macaques (RMs), a species characterized by progression to AIDS, and natural host sooty mangabeys (SMs), a species which remains AIDS free, has become a useful tool for identifying mechanisms of human immunodeficiency virus (HIV) disease progression. One such distinguishing feature is that CD4(+) central memory T (TCM) cells in SIV-infected SMs are less infected than the same cells in RMs. Here we investigated whether lower levels of infection in SMs translate into a better-preserved CD4(+) TCM compartment. We found that the CD4(+) TCM compartment is significantly more stable in SIV-infected SMs. Likely to compensate for this cell loss, we also found that CD4(+) TCM cells increase their level of proliferation upon SIV infection in RMs but not in SMs, which mechanistically supports their preferential infectivity. Our study provides new insights into the importance of long-term maintenance of CD4(+) TCM homeostasis during HIV/SIV infection.