Treatment of mice with the immunomodulator pyran copolymer inhibited leukemogenesis produced by Friend leukemia virus (FLV) complex, as evidenced by inhibition of the spleen focus-forming virus and lymphatic leukemia virus, as well as by a significant decrease in splenomegaly. In this report we present data suggesting that the protective effect of pyran is mediated by macrophages. Protection was conferred on normal recipient mice when peritoneal exudate cells from pyran-treated mice were transferred to recipient mice infected 24 hr later with FLV. Animals receiving pyran-activated peritoneal cells had a significant reduction of splenomegaly and of titers of spleen focus-forming virus and lymphatic leukemia virus than did control animals. In contrast, when glycogen-elicited peritoneal exudate cells were transferred, the mice were not protected. Pyran-activated peritoneal cells, but not normal peritoneal cells, also inhibited FLV growth in vitro. Serum from pyran-treated, but not glycogen-treated, mice also transferred resistance to FLV-infected mice.