In this study, we examined the protective and therapeutic efficacy of the immunoadjuvant CpG in combination with dendritic cell (DC) immunotherapy in a murine melanoma model. We found that murine bone-marrow derived DC stimulated in vitro with CpG displayed both enhanced expression of maturation markers and secretion of IL-12p70 and IL-10. In addition, these matured DC demonstrated enhanced ability to stimulate antigen specific CD4+ and CD8+ T cell responses in vitro. In a protection model, C57BL/6 mice vaccinated with either antigen-pulsed immature or CpG matured DC were unable to reject a lethal B16 melanoma challenge. In contrast, long-term protection was achieved in mice vaccinated with both CpG and antigen-pulsed DC, which correlated with an enhanced antigen specific T cell immune response. In a therapeutic model of established subcutaneous B16 melanoma, C57BL/6 mice treated intratumorally with CpG and B16 lysate-pulsed DC demonstrated a reduced tumor burden and prolonged survival. In a similar model of established subcutaneous tumor, mice treated with CpG-matured DC pulsed with a melanoma peptide, TRP-2, alone were unable to achieve tumor regression. Conversely, mice that received the combined vaccine of CpG and peptide-pulsed DC displayed a reduced tumor burden. These experiments provide evidence that combined immunization with both antigen-pulsed DC and the immunoadjuvant, CpG, can lead to tumor regression and long-term survival in a murine B16 melanoma model.