The purpose of this study is to evaluate the efficacy of a dose-escalated, accelerated, and hyperfractionated radiotherapy schedule with a concomitant single dose of mitomycin C in the treatment of patients with advanced laryngeal or hypopharyngeal cancer. Twenty-one previously untreated patients with advanced squamous cell carcinoma (stage III, n = 6; stage IV, n = 15) were treated with a biweekly dose-escalated, accelerated, and hyperfractionated schedule up to a total dose of 74.4 Gy in 54 fractions over 5 weeks. A single dose of intravenous mitomycin C 10 mg/m2 was given on day 30. The median follow-up after treatment of surviving patients is 48 months (range, 28 to 61 months). All patients showed complete tumor control at the primary site when evaluated 2 months after chemoirradiation by laryngomicroscopy or hypopharyngoscopy and radiologic imaging (CT, MRI). Two laryngectomies were carried out after given therapy: 1 for residual cancer and 1 for suspected residual cancer. After a median follow-up of 43 months (range, 28 to 61 months), a local control rate of 70% and disease-free survival (DFS) rate of 60% were achieved in the laryngeal cancer patients; in patients with hypopharyngeal cancer, the corresponding figures were 64% (82% after salvage surgery) and 36%. The results are promising and warrant comparison with other chemoradiotherapy regimens.