In Stage III/IV head and neck squamous cell carcinoma of the head and neck, multidisciplinary treatment is not standardized. This study evaluated preoperative simultaneous radiation therapy and Cisplatin 20 mg/M 2 /4 days during weeks 1, 4, and 7 of irradiation (CTRT).Records of 143 CTRT and 48 patients treated with other surgery/radiation/chemotherapy regimens (CONTROL) were reviewed. Chi-square, analysis of variance, and Kaplan–Meier statistical analysis were performed.CTRT improved outcomes in Grade 2 to 5 toxicity (76% CONTROL vs 45% CTRT, P < .0001), complete clinical response (68% CTRT vs 36% CONTROL, P < .003), histologic complete response (67% in CTRT vs 28% in CONTROL, P = .0002), recurrence (33% in CTRT vs 66% in CONTROL, P = .0007), and distant metastases (2% CTRT vs 37% CONTROL, P = .0003); Kaplan–Meier disease-free survival was 65% CTRT versus 34% CONTROL.CTRT increases complete clinical response, histologic complete response, organ preservation, and survival, with lower recurrence and reduced toxicity and rare recurrence. CTRT may be the first treatment for Stage III/IV head and neck squamous cell carcinoma of the head and neck.