Pyran copolymer (NSC 46015) therapy markedly enhanced host resistance to a murine lung carcinoma (M109) implanted s.c. Multiple dose schedules were not significantly better than single doses at increasing lifespan. Although tumor necrosis was much more extensive in the lesions of pyran-treated mice, pyran copolymer was not directly toxic to M109 cells in vitro. A comparative histopathological study revealed an intense histiocytic reaction in the connective tissue surrounding the primary tumor in mice receiving pyran as compared to 0.9% NaCl solution-treated controls. Macrophages were often associated with necrobiotic tumor cells. Morphologically activated macrophages were recovered from pyran-treated animals which potently inhibited DNA synthesis of M109 tumor cells in vitro. This response peaked 6 days after drug treatment and was to a large extent specific for neoplastic cells. Our results from both in vivo and in vitro studies support the concept that pyran enhances host resistance to neoplasia by mobilization and activation of the reticuloendothelial elements of the host's defense.