Idiotype protein (Id) secreted by myeloma cells is the best-characterized tumor-specific antigen and is widely used in clinical trials of immunotherapy in B-cell tumors. In this study, we used a myeloma murine model to compare the efficacy of two commonly used vaccines in human trials, Id-keyhole limpet hemocyanin (KLH) protein versus Id-KLH-pulsed DC vaccines in preventing or treating myeloma and priming tumor-specific immune responses. Although both vaccines were able to protect mice from developing myeloma, only the DC vaccine induced therapeutic immunity in tumor-bearing mice. DC vaccinations not only retarded tumor growth but also eradicated established myeloma in 60% of mice. The therapeutic efficacy of the DC vaccine was associated with increased tumor-specific IFN-g and IL-4 T-cell responses and cytolytic activity of splenic T cells. Moreover, the vaccines induced tumor-specific immune responses that protected surviving mice from tumor rechallenge. Thus, our results demonstrate that Id-based DC vaccine but not Id-KLH protein vaccine can be therapeutic to established myeloma. Further studies are needed to optimize methods of DC-based vaccines to improve the efficacy of clinical trials.