Mice bearing syngeneic plasma cell tumors are characterized by elevated numbers of granulocyte-macrophage progenitors (GM-CFU) in the spleen. We investigated the role of syngeneic plasmacytomas in the hematologic response to tumor cell transplantation by assaying the production of granulocyte-macrophage colony-stimulating activity (GM-CSA) by cultured spleen cells of tumor-bearing mice and by plasmacytoma cells, alone and in coculture with spleen cells. Elevated levels of GM-CSA were detected in 7-day culture supernatants of spleen cells from Balb/c mice transplanted 2 weeks previously with syngeneic 4T00.1 plasmacytoma cells. Colony assays of spleen cells from tumor-bearing mice demonstrated the presence of both granulocyte-macrophage and tumor cell colonies. A high frequency of GM-CFU was detected in cultures which had not been supplemented with an exogenous source of GM-CSA. Significant levels of GM-CSA were detected in media conditioned by 4T00.1 plasmacytoma cells. 4T00.1-conditioned medium did not stimulate the growth of primative erythroid (BFU-E) and multilineage (CFU-GEMM) colonies, but stimulated the growth of FDC-P1 cells, thereby establishing the activity produced by 4T00.1 cells as GM-CSF. The levels of GM-CSA in media conditioned by coculturing control spleen and 4T00.1 cells were significantly higher than those detected in media conditioned by spleen cells alone. The colony frequency induced by the coculture supernatants, however, did not exceed the sum of the colonies detected in marrow cell cultures stimulated with media conditioned by control spleen and 4T00.1 cells alone. Our findings demonstrate that murine plasmacytoma cells are capable of secreting GM-CSF. They further suggest a key role for GM-CSA production by tumor cells in the hemopoietic response of mice bearing syngeneic plasma cell tumors.