BACKGROUND.: This phase II study tested the addition of the oral epidermal growth factor receptor gefitinib to multiagent concurrent chemoradiotherapy regimen in head and neck squamous cell cancer (HNSCC). METHODS.: Patients with stage III–IV HNSCC received hyperfractionated radiation (72–74.4 Gy at 120 cGy twice daily), with concurrent 96-hour infusions of cisplatin 20 mg/m/day and fluorouracil 1000 mg/m/day given during weeks 1 and 4. Daily gefitinib 250 mg was started on day 1 of radiation and continued for 2 years. Results were retrospectively compared with our previous study using identical chemoradiotherapy without gefitinib. RESULTS.: Sixty patients were enrolled in the study; 80% had stage IV disease and 68% had oropharyngeal primary tumors. The full course of gefitinib was not tolerated by 42%; there were 5 treatment-related deaths (8%). With a median follow-up of 54 months, 2- and 3-year overall survival estimates were 80% and 71%, respectively. Projected distant metastatic control at 2 and 3 years was 88%. When compared with our historical cohort, acute toxicities including renal dysfunction and unplanned rehospitalization were worse in the study patients. Projected outcome estimates did not differ between the 2 cohorts. CONCLUSIONS.: Addition of gefitinib to concurrent chemoradiotherapy was difficult to complete, did not improve outcomes, and increased toxicity.