The hyperacute immune response observed in humans after xenotransplantation is mainly induced by the alpha(1,3)Galactosyl (alphaGal) epitopes expressed on xenografts and the pre-existing anti-alphaGal antibodies that recognize these epitopes. Based on this hyperacute rejection, we hypothesized that human cancer cells genetically modified to express the alphaGal epitope could provide a new anti-cancer vaccine. This hypothesis was previously studied using the alpha1,3-galactosyltransferase knockout (alphaGT KO) mouse model and B16 melanoma cells genetically modified to express alphaGal epitopes (B16alphaGal). In this model, the B16alphaGal vaccine showed efficacy in treating pre-existing subcutaneous and pulmonary alphaGal-negative B16 melanomas in mice. Furthermore, adoptively transferred lymphocytes from mice vaccinated with the B16alphaGal vaccine elicited a therapeutic response in mice bearing pulmonary tumors. In an attempt to increase the efficacy of the B16alphaGal vaccine, in the present study, IL-15-expressing vaccine cells (B16IL-15) were administered to mice in combination with the B16aGal vaccine with or without B16N/V vaccine cells (irradiated B16F0 melanoma cells). As documented in literature, IL-15 stimulates the proliferation and maintenance of memory CD8+ T cells. We exploited these effects of IL-15 in preventive and therapeutic experiments, wherein B16 tumors were implanted either subcutaneously or intravenously in alphaGT KO mice. In all the efficacy studies, the combination therapy showed efficacy in vaccinated mice versus control mice receiving no vaccination. In three out of five in vivo experiments, mice receiving the combination therapy were more effectively treated for B16 melanomas compared to mice receiving B16alphaGal vaccine (with or without B16N/V vaccine). Moreover, long-term memory CD8+ T cells adoptively transferred from mice receiving the combination therapy successfully treated mice with pulmonary B16 melanomas. In vivo 5,6-carboxyfluorescein diacetate, succinimidyl ester (CFSE) labeling experiments demonstrated that mice receiving the combination therapy developed CD8 + T cells which proliferated to a greater degree than CD8+ T cells from mice vaccinated with B16alphaGal plus B16N/V vaccine. In conclusion, the results obtained in this study using the described murine system demonstrate a trend supporting the hypothesis that a combined therapy of B16alphaGal plus B16IL-15 vaccines provides a potential improved treatment outcome compared to the B16alphaGal vaccine alone.