IL-15 plays many important roles within the immune system. IL-15 signals in lymphocytes via trans presentation, where accessory cells such as macrophages and dendritic cells present IL-15 bound to IL-15Rα in trans to NK cells and CD8+ memory T cells expressing IL-15/IL-2Rβ and common γ chain (γc). Previously, we showed that the prophylactic delivery of IL-15 to Rag2−/−γc−/− mice (mature T, B, and NK cell negative) afforded protection against a lethal HSV-2 challenge and metastasis of B16/F10 melanoma cells. In this study, we demonstrated that in vivo delivery of an adenoviral construct optimized for the secretion of human IL-15 to Rag2−/−γc−/− mice resulted in significant increases in spleen size and cell number, leading us to hypothesize that IL-15 signals differently in myeloid immune cells compared with lymphocytes, for which IL-15/IL-2Rβ and γc expression are essential. Furthermore, treatment with IL-15 induced RANTES production by Rag2−/−γc−/− bone marrow cells, but the presence of γc did not increase bone marrow cell sensitivity to IL-15. This IL-15–mediated RANTES production by Rag2−/−γc−/− bone marrow cells occurred independently of the IL-15/IL-2Rβ and Jak/STAT pathways and instead required IL-15Rα signaling as well as activation of JNK and NF-κB. Importantly, we also showed that the trans presentation of IL-15 by IL-15Rα boosts IL-15–mediated IFN-γ production by NK cells but reduces IL-15–mediated RANTES production by Rag2−/−γc−/− myeloid bone marrow cells. Our data clearly show that IL-15 signaling in NK cells is different from that of myeloid immune cells. Additional insights into IL-15 biology may lead to novel therapies aimed at bolstering targeted immune responses against cancer and infectious disease.