A 15,500 molecular-weight fraction of a pyran copolymer, (MVE-2) was investigated for its therapeutic efficacy against artificial lung metastases of a weakly immunogenic spontaneous fibrosarcoma (NFSa), a relatively strongly immunogenic fibrosarcoma (FSa), a moderately immunogenic spontaneous mammary carcinoma (MCa-K-, and a weakly immunogenic spontaneous mammary carcinoma (MDAH-MCa-4) syngeneic to C3Hf/Kam mice. In addition, the therapeutic efficacy of this polyanionic compound against spontaneous lung metastases of NFSa was also determined. Systemic i.v. or i.p. application of MVE-2 in doses ranging from 10 to 50 mg/kg body weight greatly reduced the number of artificial NFSa lung metastases and prolonged the survival of the mice. Multiple injections of MVE-2 given at weekly intervals were more effective than were single treatments. Although various treatment schedules with MVE-2 were capable of reducing the number of metastases and prolonging survival of tumor-bearing mice, no cures were observed. A therapeutic effect was also evident against spontaneous lung metastases of NFSa. The effect, however, was more profound when MVE-2 was given before rather than after surgical removal of the primary tumor. MVE-2 was not effective in mice exposed previously to whole-body or local thoracic irradiation. In contrast, MVE-2 protected mice against enhancement of lung metastases induced by exposure of the mice to these irradiations. NFSa growing i.m. promoted the formation of lung metastases from tumor cells given i.v. This concomitant enhancement of metastases was abolished by treatment of the mice with MVE-2. MVE-2 was also effective against tumor deposits in the other three tumors. The extent of its therapeutic efficacy was independent of tumor immunogenicity. These results suggest several approaches to the clinical application of MVE-2 and provide additional data on the therapeutic activity of the pyran copolymer derivatives in different animal models.