In a previous study we showed that immunization with dendritic cells (DC) pulsed with idiotype (Id) fused with CD40 ligand (CD40L) could break the tolerance to Id which is expressed on B lymphoma cells and restored the responsiveness of T_h cells, and, subsequently, induced IgG antibody response. However, this treatment had no therapeutic effect. In the present study, we found that using a hydrodynamic transfection‐based technique, a high level of IL‐12 production was noticed as early as 7 h after administering plasmid encoding IL‐12 (pIL‐12) and persisted at a detectable level for at least 9 days. In evaluating the efficacy of DC‐based and/or IL‐12 gene‐based therapy in the treatment of 38C13 B cell lymphoma, it was found that either treatment alone was ineffective. However, a combined treatment induced 100% long‐term survival. Furthermore, a long‐lasting anti‐tumor immunity was induced in these mice which resisted further tumor challenge at 58 days after initial inoculation. The surviving mice showed a strong IFN‐γ‐producing T_h cell response and humoral antibody response, but there were no detectable cytotoxic T lymphocytes. The antibody from the immune sera mediated a complement‐dependent lysis of tumor cells that was tumor specific. Furthermore, immunization of mice with DC‐based vaccine and pIL‐12 treatment elicited higher levels of anti‐Id IgG titer and an enhanced IgG2a response which increased the efficacy in mediating 38C13 tumor lysis. On examining the mechanism for this isotype change, we found that IFN‐γ production by CD4⁺ T cells is not the only determining factor for achieving a successful therapy. DC‐based treatment alone could induce the increase of IFN‐γ production, but lacked any therapeutic effect. The deciding factor appears to be the abrogation of IL‐4 production that was achieved by combing with IL‐12 gene therapy. Our study provides a basis for exploring the combined use of cytokines or cytokine genes in DC‐based treatment for achieving effective cancer immunotherapy.