IL-15 plays a crucial role in innate defense against viral infections. The role of IL-15 in the generation and function of adaptive immunity, following mucosal immunization, against genital HSV-2 has not been studied. Here, we report that immunized IL-15(-/-) mice were able to generate antibody and T cell-mediated immune responses against HSV-2, comparable to those seen in immunized B6 mice. However, immunized IL-15(-/-) mice were not protected against subsequent HSV-2 challenge, compared to B6 immunized mice, even with a ten times lower challenge dose. We then examined if the adaptive immune responses generated in the absence of IL-15 could provide protection against HSV-2 in an IL-15-positive environment. Adoptive transfer of lymphocytes from immunized IL-15(-/-) to naive mice were able to provide protection against HSV-2 challenge similar to protection with immunized cells from control mice. This suggests that the adaptive immune responses raised in the absence of IL-15 are functional in vivo. Reconstitution of the innate components, particularly IL-15, NK cells and NK cell-derived IFN-gamma, in immunized IL-15(-/-) mice restored their protective adaptive immunity against subsequent genital HSV-2 challenge. Our results clearly suggest that innate antiviral activity of IL-15 is necessary for protective adaptive immunity against genital HSV-2 infection.