IL-2 and IL-6 are important cytokines which have potent antitumor effects and can cooperate to induce immune responses more effectively. IL-2 gene or IL-6 gene-transfected tumor cells exhibited reduced tumorigenicity and decreased metastatic potential. In order to increase the therapeutic efficacy of IL-2 gene-, IL-6 gene-modified tumor vaccines, the experimental pulmonary metastatic melanoma-bearing mice were treated with inactivated IL-2 gene-transfected tumor cells and inactivated IL-6 gene-transfected tumor cells. After the combined vaccination, the pulmonary metastases were reduced more significantly and the survival time of tumor-bearing mice was also markedly prolonged. The CTL activity, NK activity and IL-2-induced LAK activity, IL-2 and TNF secretion from the splenocytes of the above tumor-bearing mice increased more significantly than that of tumor-bearing mice vaccinated with IL-2 gene-transfected vaccine or IL-6 gene transfected vaccine alone. These results demonstrated that the combined use of IL-2 gene-transfected tumor vaccine and IL-6 gene-transfected tumor vaccine could achieve more potent antitumor effect via more effective activation of specific and non-specific antitumor immune responses.