The aims of this study were to establish the feasibility and toxicity of the biochemical modulation of the cisplatin (CDDP)-5FU combination by interferon alpha-2b (INF), and to assess its therapeutic efficacy in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The mandatory eligibility criteria included histologically proven SCCHN; a performance status <2; adequate bone marrow, hepatic, renal, and cardiac functions; and measurable and/or evaluable disease. The protocol was CDDP, 100 mg/m2 i.v. day 1; 5-FU, 1,000 mg/m2 in a c.i.v. infusion over 96 h; and INF 3.10(6) U/day s.c., begun 2 h before cisplatinum for 5 consecutive days, repeated every 3 weeks. Twenty patients were included and received 76 cycles (median number cycles/patient = three). Eighteen patients were evaluable for activity with an overall response rate (RR) of 30% [2 complete responses (CR) + 4 partial responses (PR)], which was 55% (5/9) in previously untreated and 9% (1/11) in previously treated patients. Myelosuppression (50%), mucositis (40%), loss of electrolytes (15%), and asthenia (20%) were the most frequent severe toxic effects. Notwithstanding, the protocol was feasible and well tolerated in this overall population with a poor prognosis. Median duration of response was 8 months, and median survival for the overall population was 8.5 months. This schedule is the test arm of an ongoing international multicentric phase III trial versus standard CDDP-5FU in the same SCCHN population.