Systemic chemotherapy with 5-fluorouracil (5-FU) has been the mainstay of treatment for patients with metastatic colorectal carcinoma. Administering the drug in a continuous low-dose schedule has produced better result than bolus therapy. Resistance to short-pulse treatment can also be overcome by prolonged exposure. Recent studies suggest the feasibility of biomodulation of 5-FU with recombinant interferon (rIFN alpha-2a) with improved response. Sixteen patients were treated with continuous 5-FU 250 mg/m2 and rIFN alpha-2a 10 x 10(6) u thrice weekly for a maximum of 24 weeks. Five of them had received bolus 5-FU previously. Nine (82%) of the chemonaive group and 1 (20%) previously treated patient had partial response. The median duration of response was 7 months. Grade II to III mucositis were seen in 44% of the patients and 2 patients developed neurological complications. Although the overall response appeared encouraging, the incidence of toxicity was high. In the absence of further phase III studies, rIFN alpha-2a biomodulation of 5-FU cannot be regarded as standard treatment for patients with metastatic colorectal carcinoma.