Two different doses of gefitinib, administered along with standard radiation therapy, were tested in locally advanced inoperable head and neck cancer with the aim of finding the maximum tolerated dose and assessing the toxicity and activity of the combination. The standard '3+3' design was used for the phase I study. Radiation therapy was given according to conventional dose and schedule. Gefitinib dose escalation was stopped if more than one-third of patients of a given cohort had dose-limiting toxicity. Dose-limiting toxicity was observed in three of four patients treated at the dose of 500 mg, and included grade 3 stomatitis in three patients and grade 3 liver toxicities in one patient. The dose level of 250 mg was recommended for the phase II study. Six confirmed objective responses were observed among 16 patients. Our results do not support further trials with gefitinib and radiation therapy, according to our schedule, in this patient population. Integration of gefitinib within chemoradiotherapy regimens and combination with other biological therapies may represent the next challenge.