PURPOSE An increasing proportion of patients with head and neck cancer have no history of smoking. The purpose of this analysis was to compare the clinical outcomes between patients without a history of smoking (never-smokers) and those with a previous history of smoking (ever-smokers) treated by radiation therapy. METHODS AND MATERIALS Seventy patients with newly diagnosed squamous cell carcinoma of the oropharynx or oral cavity without a previous history of smoking were matched to a control ever-smoker with a positive tobacco history (>10 pack-years) based on age, gender, ethnicity, Karnofsky Performance Status, primary tumor site, disease stage, primary treatment, radiation dose, and start date. Outcome was compared using Kaplan-Meier analysis. Normal tissue effects were graded according to the Radiation Therapy Oncology Group/European Organization for the Treatment of Cancer radiation toxicity criteria. RESULTS With a median follow-up of 33 months, lifelong never-smokers had an increased 3-year overall survival (86% vs. 69%), disease-free survival (82% vs. 65%), and local-regional control (85% vs. 70%) compared with the ever-smoker control population (P < 0.05, for all). These differences remained statistically significant when patients treated by postoperative or definitive radiation therapy were analyzed separately. The incidence of grade 3+ complications was also significantly lower among never-smokers compared with ever-smokers (10% vs. 29%, P = 0.01). CONCLUSIONS Prognosis differed significantly between never-smokers and ever-smokers with head and neck cancer treated by radiation therapy. Further studies analyzing the biologic and molecular reasons underlying these differences are planned.