Our study evaluated the effectiveness of neoadjuvant chemotherapy and concomitant chemotherapy with radiotherapy compared to standard surgery and radiation therapy in patients with resectable stage III/IV head and neck squamous cell carcinoma. Forty-two eligible patients received neoadjuvant chemotherapy (cisplatin 100mg/m
2
intravenously day 1, and 5-fluorouracil 1g/m
2
/day continuous infusion days 1–5 every 3 weeks for 3 courses) followed by radiotherapy (65–70 Gy in 32–39 fractions to the primary site and lymph nodes; 50 Gy in 25–28 fractions to areas at risk) and concomitant chemotherapy (cisplatin 80mg/m
2
intravenously every 3 weeks starting on day 1 of radiotherapy). Neoadjuvant therapy induced grade 4 cytopenias (12/42 patients) and grade 4 gastrointestinal toxicities (7/42 patients). Concomitant radiochemotherapy-induced grade 4 toxicities (6 patients). Neoadjuvant chemotherapy biopsy-proven complete responses were 15 of 42 patients (36%), partial responses in 23 of 42 patients (55%), and an overall response rate of 91%. Thirty-seven of 38 responders received concomitant radiochemotherapy. Complete responses in 35 of 42 patients (83%), partial response in 7 of 42 patients (7%), and overall response in 90%. The 3-year disease-free and overall survival for chemotherapy plus radiotherapy versus surgery plus radiotherapy: 61% versus 43% (P = 0.17) and 71% versus 43% (P = 0.02). These data suggest that a randomized trial of concomitant radiochemotherapy versus neoadjuvant plus concomitant radiochemotherapy should be considered. EBM rating: B-2.