Previous studies have indicated that the cytokine interleukin (IL)-21 may induce both innate and adaptive immune responses against tumors. The goal of this study was to evaluate a new adoptive immunotherapy strategy that combined lymphocytes from mice immunized with a murine myeloma vaccine secreting murine IL-21 (mIL-21-Sp2/0) in lymphopenic mice induced by cyclophosphamide. The data indicate that effective antitumor immunity was induced in mice receiving syngeneic murine lymphocytes from the mice immunized with the mIL-21-Sp2/0. More importantly, the efficacy against the Sp2/0 cell challenge was enhanced after the lymphocytes were activated and proliferated ex vivo before administration into the lymphopenic mice. We conclude that the adoptive transfer of tumor antigen-specific lymphocytes into mice immunized with mIL-21-Sp2/0 induced protective immune responses against myeloma challenge.