The tumor cells can be recognized and eliminated by the power of the immune response has result in intense interest in the development of tumor vaccines transfected with plasmid DNA containing target genes, and the tumor vaccines are being evaluated as prophylactic and therapeutic vaccines for tumor. In current study, we designed a murine myeloma cell (SP2/0) vaccine containing mIL-21 plasmid DNA and to evaluate its anti-tumor efficacy and analyze the mechanism of anti-tumor efficacy. It was upregulated obviously that the MHC-I molecule was expressed on SP2/0-mIL-21 tumor cells surface and the significant tumor regression and prolonged survival were observed in BALB/c mice injected with the SP2/0-mIL-21 tumor vaccine. The four mice without tumors growth were rechallenged with SP2/0 cells on the opposite site of the back and there was only one with growth a small tumor after 30 days and others remained tumor free. The cytotoxic activities of NK, CTLs and the IFN-gamma; were significantly increased respectively in immunized mice. The expression of I-TAC in the tumor tissue was upregulated and the tumor tissue were showed the tumor cells were apoptosis and a lots of infiltrating lymphocytes and phagocytes. We conclude that the autologous IL-21-producing tumor vaccine can induce strong cell-mediated immune response and it is a promising immune adjunctive modality to prevent or inhibit growth of SP2/0 cells in mice model.