To date no effective salvage regimens have been reported for progressive or relapsed patients with advanced colorectal cancer, and new potentially active drugs or combinations should be evaluated for these situations. In vitro studies have suggested that lonidamine (LND) positively modulates the cytotoxic activity of mitomycin (MMC) in human colon cancer cell lines. From November 1993 to February 1995, 29 colorectal cancer patients previously treated with first line chemotherapy were admitted to the study. Treatment consisted of a combination of MMC at 12 mg/m2 administered intravenously on day 1, and LND at 150 mg per os three times daily for five consecutive days, starting two days before MMC; the treatment was repeated every four weeks for a total of 109 cycles. All patients were fully evaluable for response and toxicity. Two partial responses (7%), 10 stable disease, and 17 progressive disease were observed. Median survival duration was 212 days. Toxicity was mild, with no WHO grade 3-4 toxicity. MMC + LND combination therapy does not seem to be effective in previously treated advanced colorectal cancer patients.