Improved response rates in metastatic colorectal carcinoma recently have been observed for the combination of 5-fluorouracil (5-FU) and recombinant interferon alfa-2a (rIFN), compared to those obtained in historical trials of single-agent 5-FU. The mechanism of interaction between these agents has not been explored adequately but may relate to biochemical modulation of 5-FU by rIFN. Toxicities resulting from this combination have included fever, chills, myalgias, granulocytopenia, mucositis, diarrhea, skin rash, neurological symptoms, and hand-foot syndrome. Future studies of 5-FU with rIFN should investigate schedules aimed at reducing toxicity without compromising efficacy and also should explore mechanisms of enhanced activity.