BACKGROUND Potential synergy between 5-fluorouracil (5-FU) and interferon alpha-2a (IFN-alpha-2a) has been demonstrated in the treatment of colorectal carcinoma. Continuous low-dose infusion of 5-FU may have superior response rates to bolus 5-FU in these malignancies. This report presents results of two Phase II trials using these principles in colorectal cancer. METHODS Forty-eight patients were entered onto two protocols; 18 were treated with 5-FU by a bolus infusion schedule with concurrent IFN-alpha-2a (Group 1). Thirty patients were treated with continuous low-dose 5-FU and IFN-alpha-2a thrice weekly (Group 2). RESULTS The overall response rates were 33% (95% confidence interval [CI], 16-68%) and 33% (95% CI, 17-53%), respectively, for Groups 1 and 2. In Group 2, in 16 previously untreated patients, there was a response rate of 56% (95% CI, 30-80%). The median survival was 11 months and 6 months for Groups 1 and 2, respectively. Toxicity in Group 1 was as expected, except the incidence of central nervous system toxicity was low, with only one patient requiring dose reduction because of cerebellar ataxia. The toxicity in Group 2 was substantial, with four patients being removed from study because of toxicity and all patients treated for more than 2 months requiring dose reductions. The most common (67%) toxicity was mucositis, with 33% of those patients classified as Grade III or IV (Southwest Oncology Group criteria). Other major toxicities were fatigue and hand/foot syndrome. CONCLUSIONS The first trial confirms previous response rate data for bolus injection 5-FU and IFN-alpha-2a. The second trial of low-dose continuous infusion 5-FU with IFN-alpha-2a demonstrates similar efficacy with substantially greater toxicity.