Because of the different sites and mechanisms of biochemical interaction among 5-fluorouracil (5-FU), leucovorin (LV) and interferon (IFN), we hypothesized that the concomitant use of IFN could increase the activity of the 5-FU/LV combination in colorectal cancer patients. Forty-five patients were included in the study and all were evaluable for response and toxicity. They were treated with 5-FU 370 mg/sqm i.v. d 2-6; LV 200 mg/sqm i.v. d 2-6; IFN alpha 2b 3 million U im d 1-7 every 21 days. Six patients achieved complete responses, 17 partial responses, 14 had stable disease and 8 progressed on therapy for an overall response rate of 51%. Median survival has not been reached. At a median follow-up of 14 months 33 of 45 patients remain alive. Nine patients experienced toxicity grade 3 (6 diarrhea and 3 stomatitis). Our results seem to suggest that IFN could increase 5-FU/LV activity and that this combination is well tolerated.