BACKGROUND Recurrent cancer of the head and neck after primary therapy is almost always fatal. The combination of 5-fluorouracil (5-FU) and cisplatin is considered the best available therapy but complete response rates remain too low to affect survival. This study was designed to evaluate the complete response rate and toxicity of 5-FU, cisplatin, and alpha-interferon (alpha-IFN) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). METHODS Fifty eligible patients with recurrent or metastatic SCCHN and no prior chemotherapy (40 men, 10 women; age range, 26-77 years; median, 59 years; 82% white; 88% had prior surgery and 92% had prior radiation therapy) were treated every 21 days with 96-hour infusion of 5-FU 1000 mg/m2/day; cisplatin 100 mg/m2, day 1; and alpha-IFN 5 x 10(6) units/day, days 1-4. RESULTS One hundred fifty-seven courses of chemotherapy were administered, with a median of three courses. Thirty-seven patients experienced Grade 3 or 4 toxicity. Of the 17 patients with Grade 4 toxicity; 12 had hematologic toxicity, 3 stomatitis, and 2 vomiting. Two additional patients died of myelosuppression-related sepsis. Of the 50 patients, 3 (6%) achieved a complete response, five (10%) had a partial response, 3 (6%) had unconfirmed response (1 complete and 2 partial), 10 (20%) had stable disease, 17 (34%) progressed, and 12 (24%) were considered nonresponders owing to early death (6) or inadequate assessment (6). The median survival was 5 months. CONCLUSIONS The complete response rate of patients with recurrent or metastatic SCCHN treated with 5-FU, cisplatin, and alpha-IFN does not appear to be superior to that observed for 5-FU and cisplatin. Alpha-interferon appears to augment hematologic and gastrointestinal toxicities associated with this combination.