Bone marrow (BM) is the key hematopoietic organ in mammals and is involved in the homeostatic proliferation of memory CD8 + T cells. Here we expanded on our previous observation that BM is a preferential site for T-cell proliferation in simian immunodeficiency virus (SIV)-infected sooty mangabeys (SMs) that do not progress to AIDS despite high viremia. We found high levels of mature T-cell proliferation, involving both naive and memory cells, in healthy SMs and rhesus macaques (RMs). In addition, we observed in both species that lineagespecific, BM-based T-cell proliferation follows antibody-mediated in vivo CD4 + or CD8 + T-cell depletion, thus indicating a role for the BM in maintaining T-cell homeostasis under depleting circumstances. We also observed that, in SIVinfected SMs, but not RMs, the level of proliferation of BM-based CD4 + T cells is higher than that of circulating CD4 + T cells. Interestingly, limited BM-based CD4 + T-cell proliferation was found in SIV-infected SMs with low CD4+ T-cell counts, suggesting a regenerative failure in these animals. Collectively, these results indicate that BM is involved in maintaining T-cell homeostasis in primates and suggest a role for BM-based CD4 + T-cell proliferation in determining the benign nature of natural SIV infection of SMs. copy; 2009 by The American Society of Hematology.