OBJECTIVE To determine whether interferon: alpha 2b can improve results of 5-fluorouracil adjuvant treatment of Dukes C colorectal cancer patients, we compared the outcome of patients receiving a fluorouracil-interferon combination to that of historic controls treated with fluorouracil alone. METHODS Fifty-seven Dukes C colorectal cancer patients were given 5-fluorouracil-interferon-alpha 2b adjuvant treatment from October 1986 to September 1990. The results were compared with those obtained in 51 consecutive patients treated at the same institutions with 5-fluorouracil (5-FU) alone (used at the same doses and schedule) between 1983 and 1986. The main prognostic variables were similar in the two groups. RESULTS No life-threatening toxicity occurred in either group. The addition of interferon (IFN) slightly impaired tolerance to the treatment; however, the dose of IFN had to be reduced only in five patients and discontinued in one patient. Grade 3 and 4 myelotoxicity was rare and not substantially different in the two groups. Interferon-related side effects (fever, flu-like syndrome, malaise, etc.) were frequent, but, in general, mild or moderate. At the time of this analysis (July 1992), median follow-up was 49 (range, 20-70) months in the group of patients treated with 5-FU+IFN, and 86 (range, 68-103) months in the group receiving 5-FU alone. There were 17 recurrences and 15 cancer-related deaths among patients receiving combined treatment, and 27 deaths in the group treated with 5-FU alone. Both five-year relapse-free survival (65 percent vs. 47 percent; P = 0.043) and cause-specific survival (64 percent vs. 46 percent; P = 0.038) were significantly better in the patients receiving combined treatment. After correction for the influence of prognostic pretreatment variables, 5-FU+IFN again afforded a significant advantage in terms of both relapse-free (P < 0.01) and overall survival (P < 0.001). CONCLUSIONS 5-FU-IFN-alpha 2b treatment seems to improve the prognosis in Dukes C colorectal cancer patients.