It has been well established that chemo‐immunotherapy using cytotoxic drugs and appropriate cytokines offers a new approach to increasing the therapeutic index in the treatment of neoplastic diseases. This study investigates the efficacy of combinations of interleukin‐12 with cyclophosphamide, paclitaxel, cisplatin or doxorubicin in the murine L1210 leukemia model. Mice inoculated i.p. with 1 × 10³ or 1 × 10⁵ leukemia cells were treated with interleukin‐12 and/or chemotherapeutics, and were observed daily for survival. Immunosuppression with X‐irradiation or macrophage depletion with injections of silica were used to examine the dependence of the therapeutic effects on the efficiency of the immune system. Treatment with interleukin‐12 or one of the studied chemotherapeutics given alone resulted in moderate anti‐leukemic effects. Combination of interleukin‐12 with cyclophosphamide or paclitaxel produced no augmentation of anti‐leukemic effects in comparison with these agents given alone. Combination of interleukin‐12 with cisplatin resulted in prolongation of the survival time; however, in the experiment with mice inoculated with 1 × 10⁵ leukemia cells, no long‐term survivors (>60 days) were observed; on the contrary, combination of interleukin‐12 with doxorubicin resulted in 100% long‐term survivors. This effect was completely abrogated either by X‐irradiation of mice or by macrophage depletion. We also found that doxorubicin augments IL‐12‐stimulated production of interferon‐γ in vivo. Our observations demonstrating potentiation of the anti‐leukemic effects of the IL‐12 and doxorubicin combination suggest that the combined use of these 2 agents could be beneficial in leukemia therapy. Int. J. Cancer 77:720–727, 1998. © 1998 Wiley‐Liss, Inc.