Purpose: In this randomized, phase III study, quality of life (QoL) was assessed in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) after high-dose radiotherapy alone or in combination with cetuximab. Patients and Methods: Patients with stage III or IV nonmetastatic and measurable squamous cell carcinoma of the oropharynx, hypopharynx, or larynx were eligible. QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and EORTC QLQ Head and Neck Cancer-Specific Module at baseline, week 4, and at months 4, 8, and 12 postbaseline. Results: In this study, one of the largest conducted in a population of patients with locoregionally advanced SCCHN, 424 patients received radiotherapy alone (213 patients) or radiotherapy plus cetuximab (211 patients). Radiotherapy/cetuximab significantly improved locoregional control (P = .005) and overall survival (P = .03) compared with radiotherapy alone, without significantly increasing radiotherapy-associated adverse events. The current analysis focused on the impact of cetuximab on the QoL. Compliance with completion of QoL questionnaires was high in both arms. QoL worsened during treatment and improved after cessation of treatment, reaching baseline levels at 12 months. There were no significant differences in QoL scores between the treatment arms. This was particularly notable for global health status/QoL, social functioning, social eating, and social contact. Pretreatment global health status/QoL was identified as a significant prognostic variable in these patients. Conclusion: The addition of cetuximab to radiotherapy significantly improved locoregional control and increased overall survival without adversely affecting QoL. © 2007 by American Society of Clinical Oncology.