We investigated the mechanism(s) by which systemic administration of doxorubicin (DXR) produced growth retardation of B16 melanomas in the subcutis of syngeneic mice. DXR or saline was injected intravenously (i.v.) into C57BL/6 mice, and B16-BL6 cells were implanted subcutaneously (s.c.) on day 3, 7, or 21 after DXR treatment. In the DXR-pretreated mice, the tumors grew at a slower rate than in control (saline-treated) mice. The experiments were repeated with a B16 variant resistant to DXR with similar results. Tumor growth retardation correlated with extent of myelosuppression monitored by counting bone marrow cells, circulating leukocytes and peritoneal macrophages. In DXR-pretreated mice reconstituted with 1 x 107 viable syngeneic spleen cells, the s.c. tumors grew at a rate similar to that in control mice. DXR treatment and spleen cell reconstitution experiments were repeated in BALB/c athymic nude mice. The results were very similar. The growth of s.c. tumors was directly correlated with the degree of peritumoral vascularity. These data indicate that in addition to its well-documented direct antitumor effects, DXR may produce retardation of tumor growth by producing myelosuppression and, hence, inhibition of host cell-induced tumor angiogenesis.