The effects of DL-alpha-difluoromethylornithine (DFMO), a specific, irreversible inhibitor of ornithine decarboxylase (ODC), on tumors induced in the muscle of C57BL mice by Lewis lung (LL) carcinoma cells and on the development of lung metastases have been investigated. ODC activity and putrescine, spermidine and spermine concentrations were increased both during the early phase of development of the primary LL tumor and in the lung coinciding with the development of metastases. Oral treatment with DFMO (2% aqueous solution as sole drinking fluid, equivalent to 4 g DFMO/kg/day) decreased markedly the ODC activity and the putrescine and spermidine concentrations of the primary tumor, and stimulated S-adenosyl-L-methionine decarboxylase activity. ODC activity and putrescine and spermidine concentrations were similarly markedly reduced in the metastatic lung by DFMO treatment. By comparison with untreated controls, DFMO treatment from day 1 after inoculation resulted in an 81% decrease in tumor size and a 92% reduction of lung metastases by day 20 and prolonged the mean survival time from 20.2 to 28.8 days. The same treatment regimen started 8 days after tumor inoculation resulted in a 52% inhibition of tumor growth and an 82% reduction of lung metastases, and prolonged the mean survival time to 24.9 days. The clear antitumoral effects obtained with DFMO on this animal metastatic cancer indicate its potential value in the treatment of metastases in humans.