The combination of chemotherapy and interferons has been tested in several human tumors but, until now, no clinical data have been reported in head and neck cancer. At the Istituto Nazionale per la Ricerca sul Cancro of Genoa, 14 patients with previously treated SCC-HN underwent the following regimen: cisplatin, 20 mg/m2/day, 5-fluorouracil, 200 mg/m2/day i.v. bolus and recombinant interferon-alpha-2b (r-IFN-alpha-2b) (Intron-A, Shering-Plough), 3 MIU/day i.m., for 5 consecutive days. Recombinant IFN-alpha-2b was also administered, at the same dosage, 3 times per week during the 2 weeks interval among cycles. Grade III-IV hematological toxicity was recorded in 43% of patients. Increasing fatigue, anorexia, and flu-like symptoms were experienced by most patients. For these reasons 9 of 14 patients needed a chemotherapy delay and a r-IFN-alpha-2b discontinuation. Therefore, due to the heavy toxicity observed, accrual was terminated early. The overall response rate was 54% (31% CR, 23% PR). Among the 5 patients who never delayed chemotherapy and discontinued r-IFN-alpha-2b, all but one responded. In conclusion, a synergistic activity between chemotherapy and r-IFN-alpha-2b in head and neck cancer cannot be excluded, but, in our opinion, further investigations should consider less aggressive regimens and/or more selected patients.