Simian immunodeficiency virus (SIV) SIV_smm naturally infects sooty mangabeys (SMs) and is the source virus of pathogenic infections with human immunodeficiency virus type 2 (HIV-2) and SIV_mac of humans and macaques, respectively. In previous studies we characterized SIV_smm diversity in naturally SIV-infected SMs and identified nine different phylogenetic subtypes whose genetic distances are similar to those reported for the different HIV-1 group M subtypes. Here we report that, within the colony of SMs housed at the Yerkes National Primate Research Center, at least four SIV_smm subtypes cocirculate, with the vast majority of animals infected with SIV_smm subtype 1, 2, or 3, resulting in the emergence of occasional recombinant forms. While SIV_smm-infected SMs show a typically nonpathogenic course of infection, we have observed that different SIV_smm subtypes are in fact associated with specific immunologic features. Notably, while subtypes 1, 2, and 3 are associated with a very benign course of infection and preservation of normal CD4⁺ T-cell counts, three out of four SMs infected with subtype 5 show a significant depletion of CD4⁺ T cells. The fact that virus replication in SMs infected with subtype 5 is similar to that in SMs infected with other SIV_smm subtypes suggests that the subtype 5-associated CD4⁺ T-cell depletion is unlikely to simply reflect higher levels of virus-mediated direct killing of CD4⁺ T-cells. Taken together, this systematic analysis of the subtype-specific features of SIV_smm infection in natural SM hosts identifies subtype-specific differences in the pathogenicity of SIV_smm infection.