Twenty-two patients with metastatic colorectal cancer entered a Phase I-II trial to assess the maximum tolerable dose of alpha-2B-interferon administered intramuscularly three times per week in combination with fixed doses of 5-fluorouracil (450 mg/m2 IV for 5 days, and, from day 28, weekly) and folinic acid (200 mg/m2 IV before 5-fluorouracil) and the efficacy of this combination. Diarrhea and mucositis were the most frequent 5-fluorouracil-related toxicities and were > or = ECOG grade 3 in 23% and 18% of patients, respectively. Of 15 patients receiving interferon > or = 9 x 10(6) IU, 10 required interferon dose reduction mostly because of severe fatigue, anorexia, and declining performance status. Among 19 patients evaluable for response, 3 achieved a partial response and 1 a complete response for an overall response rate of 21% (95% confidence interval, 6-46%). In conclusion, our study demonstrates that IFN-alpha 2B at doses higher than 6 x 10(6) IU intramuscularly three times per week in the combination with 5-fluorouracil and folinic acid we used is too toxic for the majority of patients; this combination has moderate activity in metastatic colorectal cancer, although similar response rates have been reported, with less toxicity, with 5-fluorouracil plus folinic acid without IFN-alpha. A larger Phase III study would be required to determine the value of IFN-alpha in this combination.