Background. The management of recurrent unresectable head and neck cancer remains a challenging problem. Based on the circadian rhythm concept, we sought to determine the maximum tolerated dose (MTD) of infusional 5-flourouracil (5-FU), hydroxyurea (HU), and reirradiation (RT). Method. Bolus 5-FU was escalated from 300mg/m2/d to a 10-hour infusion beginning at midnight, increased at 150 mg/m2/d increments. HU, 1.5 g, remained constant. Chemotherapy was given on weeks 1 and 4. RT was given daily, 2.0 Gy per fraction on weeks 1 and 2 followed by a 1-week break, then hyperfractionated weeks 4 and 5, total dose 50 Gy. The goal was to deliver a continuous course of RT to 60 Gy after the MTD was determined with an additional week of chemotherapy. Results. Six cohorts were treated to establish the 5-FU MTD of 900 mg/m2/d. The seventh cohort received continuous RT and 5-FU, 750 mg/m2/d, one dose level below the MTD. Two hematologic, three skin, and six mucosal ≥ grade 3 toxicities were noted in 7 of 16 patients. The median survival was 10.2 months and the 1-year survival was 41%. The median survival for the entire group was 9.4 months, with a 1- and 2-year survival of 39% and 15%, respectively. Conclusion. RT can be given in a continuous fashion with concurrent 5-FU and HU. Because radiation sensitization should be achievable at nontoxic doses of 5-FU, we recommend 600 mg/m2/d in phase a II setting. © 2003 Wiley Periodicals, Inc.