Three syngeneic murine tumor models were used to determine potential interactions between chemotherapeutic drugs and the synthetic liposome-encapsulated macrophage activator, muramyl tripeptide phosphatidylethanolamine (MLV-19835). Experiments were designed to maximize any additive toxicity of the simultaneous administration of MLV-19835 on the known myelosuppressive effects of doxorubicin, ifosfamide, and cisplatin. Treatment with these drugs resulted in diminished blood leukocyte counts, altered leukocyte differentials, and decreased hematocrits, but the systemic administration of MLV-19835 produced no additional deleterious effects. Myelosuppression normally observed at 2 weeks following treatment of mice with doxorubicin was prevented by combination treatment with MLV-19835. In addition, there was no interference of the antitumor activity of ifosfamide or doxorubicin against subcutaneous, kidney, and spleen tumors. These studies and the recent demonstration of the biological activity of MLV-19835 in phase II trials of osteosarcoma recommend clinical testing of these combined modalities.