Interleukin-15 (IL-15) in vitro treatment of peripheral blood mononuclear cells (PBMC) from human immunodeficiency virus (HIV)-infected individuals specifically enhances the function and survival of HIV-specific CD8⁺ T cells, while in vivo IL-15 treatment of mice preferentially expands memory CD8⁺ T cells. In this study, we investigated the in vivo effect of IL-15 treatment in 9 SIVmac251-infected cynomolgus macaques (low dose of IL-15, 10 μg/kg of body weight, n = 3; high dose of IL-15, 100 μg/kg, n = 3; control [saline], n = 3; dose administered twice weekly for 4 weeks). IL-15 treatment induced a nearly threefold increase in peripheral blood CD8⁺CD3⁻ NK cells. Furthermore, CD8⁺ T-cell numbers increased more than twofold, mainly due to an increase in the CD45RA⁻CD62L⁻ and CD45RA⁺CD62L⁻ effector memory CD8⁺ T cells. Expression of Ki-67 in the CD8⁺ T cells indicated expansion of CD8⁺ T cells and not redistribution. IL-15 did not affect CD4⁺ T-cell, B-cell, and CD14⁺ macrophage numbers. No statistically significant differences in changes from baseline in the viral load were observed when control-, low-dose-, and high-dose-treated animals were compared. No clinical adverse effects were observed in any of the animals studied. The selective expansion of effector memory CD8⁺ T cells and NK cells by IL-15 further supports IL-15's possible therapeutic use in viral infections such as HIV infection.