Stage IV inoperable head and neck cancer has a 2-year mortality rate of greater than 70% when treated with conventional radiotherapy. A Phase II study was undertaken to evaluate the effects of concomitant chemotherapy and accelerated, interrupted, twice-a-day radiotherapy on tumor response, locoregional control, survival, and morbidity.Thirty-four patients with Stage IV inoperable squamous cell carcinoma of the head and neck and a minimum follow-up of 36 months were evaluated. Concomitant chemoradiotherapy was administered during weeks 1, 3, and 5 (with planned breaks during weeks 2 and 4), consisting of cisplatin 60 mg/m2 on day 1, continuous 5-day infusion of 5-fluorouracil, 750 mg/m2 per day, and radiotherapy, 2 Gy twice a day, more than 6 hours apart, followed by 3 days of radiation therapy alone (final "boost") in week 6, for a total dose of 70 Gy and treatment duration of 5 1/2 weeks (38 days).Twenty-seven patients achieved a clinical complete response (82%). Actuarial locoregional control at 3 years was 73% and the actuarial 3-year survival probability, including all deaths, was 38%. All locoregional recurrences were manifested within 12 months. Of the 20 deaths, 12 were tumor related (locoregional and/or metastatic), 3 were treatment related, and 5 were due to other causes. Acute toxicity consisted of grade 3 mucositis and dysphagia and grade 2-3 leukopenia, not requiring treatment interruption or cessation.Concomitant accelerated radiation therapy and chemotherapy is a feasible treatment approach in this prognostically poor patient population, yielding dramatic tumor responses and impressive locoregional control at the cost of somewhat increased acute toxicity. Although serious late complications have not been observed, caution should be exercised in view of the relatively short follow up.