The effect of partially purified rat interferon ( RIFN ) was evaluated in CC531 colon tumor-bearing rats. Tumor CC531 is a DMH-induced, transplantable adenocarcinoma exhibiting weak immunogenicity. When small tumor fragments were implanted under the renal capsule, daily treatment with RIFN for 5 days led to a highly significant (p less than 0.001) inhibition of tumor growth, measured 7 days after implantation. Cyclic treatment with RIFN (10(5) units/kg/day, for 7 days in weeks 2, 4, 6 and 8) significantly retarded the development of artificial lung metastases, induced by intravenous (i.v.) injection of 5 X 10(5) colon tumor cells. The median survival time was 177 days in the RIFN group as compared to 116 days in the control group. Three of eight animals treated with RIFN showed no sign of lung metastases when they were killed 250 days after tumor cell injection. The same cyclic RIFN treatment which was effective in the lung metastases model had no influence on the growth of liver metastases evoked by the intraportal injection of 5 X 10(5) tumor cells. Laparotomy performed at days 30 and 50 after inoculation revealed equal numbers of liver metastases in the RIFN -treated group and the control group. The mean survival times obtained in the two groups were 96 +/- 20 days and 108 +/- 14 days, respectively (0.05 less than p less than 0.10). The results indicate that (1) there is no inherent resistance of this solid tumor to RIFN therapy and (2) the effect of RIFN treatment is determined by the site of tumor development. The finding that the liver can provide a protective environment against tumor immunity may have important clinical implications.