The therapeutic efficacy of active immunization with B16‐F10.9 melanoma cells transfected with syngeneic major histocompatibility complex (MHC) class‐l genes, modified by infection with Newcastle Disease virus (NDV) or modified by both treatments, was compared. B16‐F10.9 tumor‐bearing mice were treated at various stages of tumor growth and metastasis with irradiated, modified tumor‐cell vaccines. Irradiated tumor cells and H‐2Db transfectants did not stimulate anti‐tumor immunity while H‐2Kb transfectants and NDV‐modified F10.9 cells showing low and high expression of MHC class‐l genes efficiently prevented metastasis of small established tumors. NDV‐modified parental‐cell vaccines functioned optimally and improved overall survival by about 60%, also at early stages of metastasis establishment. A synergistic effect of H‐2Kb expression and virus modification on rejection of micrometastases was observed in mice bearing advanced tumors. Postoperative vaccination of mice carrying multiple metastases with NDV‐modified vaccines caused significant, but incomplete, reduction of metastatic tumor load. The therapeutic effect of NDV‐modified tumor vaccines was dependent on multiple immune mechanisms. Depletion of CD8, CD4 or NK cells by in vivo treatment with monoclonal antibodies reversed the immunotherapeutic effects of the vaccine. Thus, tumor xenogenization and gene modification may act synergistically to vaccinate against advanced tumors, while single modalities can effectively vaccinate against metastasis at early stages of tumor growth.