Natural killer (NK) cells play an essential role in antiviral immunity, but knowledge of their function in secondary lymphoid organs is incomplete. Lymph node follicles constitute a major viral reservoir during infections with HIV-1 and simian immunodeficiency virus of macaques (SIVmac). In contrast, during nonpathogenic infection with SIV from African green monkeys (SIVagm), follicles remain generally virus free. We show that NK cells in secondary lymphoid organs from chronically SIVagm-infected African green monkeys (AGMs) were frequently CXCR5+ and entered and persisted in lymph node follicles throughout the follow-up (240 d post-infection). These follicles were strongly positive for IL-15, which was primarily presented in its membrane-bound form by follicular dendritic cells. NK cell depletion through treatment with anti-IL-15 monoclonal antibody during chronic SIVagm infection resulted in high viral replication rates in follicles and the T cell zone and increased viral DNA in lymph nodes. Our data suggest that, in nonpathogenic SIV infection, NK cells migrate into follicles and play a major role in viral reservoir control in lymph nodes.