IL-21 regulates Th17 cell homeostasis, enhances the differentiation of memory B cells and antibody-secreting plasma cells, and promotes the maintenance of CD8⁺ T-cell responses. In this study, we investigated the phenotype, function, and frequency of blood and intestinal IL-21–producing cells in nonhuman primates that are hosts of progressive (rhesus macaques [RMs]) and nonprogressive (sooty mangabeys [SMs]) SIV infection. We found that, in both species, memory CD4⁺CD95⁺CCR6⁻ T cells are the main IL-21 producers, and that only a small fraction of CD4⁺IL-21⁺ T cells produce IL-17. During chronic SIV infection of RMs, CD4⁺IL-21⁺ T cells were significantly depleted in both blood and rectal mucosa, with the extent of this depletion correlating with the loss of Th17 cells. Furthermore, treatment with IL-21 increased the in vivo levels of Th17 cells in SIV-infected RMs. In contrast, normal levels of CD4⁺IL-21⁺ T cells were found in SIV-infected SMs. Collectively, these data indicate that depletion of IL-21–producing CD4⁺ T cells distinguishes progressive from nonprogressive SIV infection of RMs and SMs, and suggest that depletion of CD4⁺IL-21⁺ T cells is involved in the preferential loss of Th17 cells that is associated with SIV disease progression. Further preclinical studies of IL-21 as a potential immunotherapeutic agent for HIV infection may be warranted.