Background In an effort to optimize nonoperative therapy in patients with locoregionally advanced head and neck squamous cell cancer, the Southwest Oncology Group conducted a phase II trial combining 3-drug taxane-containing induction chemotherapy with accelerated fractionation/concomitant boost radiation and concomitant single-agent cisplatin. Methods Two induction courses using docetaxel (75 mg/m 2 on day 1), cisplatin (100 mg/m 2 on day 1), and fluorouracil (1000 mg/m 2 /day continuous intravenous infusion days 1???4) were given, with an interval of 21 days. Patients who were stable or responded to the chemotherapy received definitive accelerated fractionation/concomitant boost radiation with concurrent cisplatin (100 mg/m 2 ) on days 1 and 22 of radiation. Results There were 74 eligible and evaluable patients enrolled between March 1, 2003, and August 15, 2004; 52 (70%) had stage IV disease. At least 1 grade 3-4 toxicity was experienced by 63 patients (85%) during induction. A total of 61 patients completed induction and began concurrent chemoradiotherapy; 50 (68%) completed all planned treatment. At least 1 grade 3-4 toxicity was noted in 53 of the 58 patients (91%) evaluated for toxicity from concurrent chemoradiotherapy. Two patients died during induction, and 2 during chemoradiation. With a median follow-up of 36 months (range, 14???50), the 2-year and 3-year overall survival estimates were 70% and 64%, with 2-year and 3-year progression-free survival estimates of 66% and 61%, respectively. Conclusions Three-drug induction chemotherapy followed by accelerated fractionation/concomitant boost radiation and concurrent cisplatin is toxic but feasible within a cooperative group. In this patient cohort with advanced head and neck squamous cell cancer, overall and progression-free survivals were encouraging, justifying further study of this approach. ?? 2009 Wiley Periodicals, Inc. Head Neck, 2010