The objective of the present investigation was to study the potentiation of antitumor and antimetastatic activities of DL-alpha-difluoromethylornithine (DFMO) by inducers of interferon, namely, tilorone and polyriboinosinic:polyribocytidilic acid complex [poly(l) X poly(C)]. The results of this study indicate that these interferon inducers enhance the antitumor activity of DFMO against B16 melanoma and Lewis lung carcinoma in mice. In B16 melanoma, DFMO, tilorone, or poly(l) X poly(C), when administered alone, showed 85, 39, and 39% of inhibition of tumor growth, respectively. However, a combination of DFMO and tilorone or poly(l) X poly(C) resulted in 98 and 95% inhibition of growth, with about 20% of animals showing no detectable tumors. This potentiation appears to be related to the ability of the compounds to induce interferon, since an analogue of tilorone, MDL 10,842, neither induced interferon nor potentiated the antitumor activity of DFMO. The data also indicate that this combination is particularly effective when the tumor burden is relatively low. When tilorone was given 7 days after tumor inoculation, it did not show any potentiation of antitumor activity of DFMO. The studies with Lewis lung carcinoma also showed that the interferon inducers potentiated both the antitumor and antimetastatic activities of DFMO. DFMO or tilorone administered alone showed 28 and 46% inhibition of tumor growth and 80 and 58% inhibition of metastases, respectively. Poly(l) X poly(C) by itself did not have any effect on the tumor growth and metastases. However, a combination of DFMO and tilorone brought about 78% inhibition of tumor growth and 99.5% inhibition of metastases, with 87% of the animals free of any metastases. A combination of DFMO and poly(l) X poly(C) also showed a potentiation of both antitumor activity (58% inhibition) and antimetastatic activity (94% inhibition), with 62% of the animals free of any detectable metastases. The mechanism underlying this tumor suppression by combination of DFMO and interferon inducers is not yet known. Enhancement of host immune response or interferon-mediated cytotoxicity could account for the observed marked suppression of tumor growth. Previous studies using interferon and the data reported here with interferon inducers, along with the relatively nontoxic nature of DFMO, suggest a potential use for the inhibitors of polyamine biosynthesis in combination with interferon or interferon inducers in cancer chemotherapy and other proliferative states.