Background: Locally advanced squamous cell cancer of the head and neck (SCCHN) is treated with curative intent, but recurrence and death are common. SCCHN frequently over-expresses EGFR (ErbB1). Co-expression of other HER family members such as HER2 (ErbB2) may contribute to resistance to EGFR inhibition, which is the only validated targeted therapy in SCCHN. Methods: The trial investigates if adjuvant afatanib, an irreversible ErbB family blocker, which has shown preclinical activity against all ErbB dimers including EGFR and HER2, reduces the risk of recurrence in high-risk patients who have no evidence of disease following platinum-based chemoradiation with or without neck dissection. Patients are eligible who have received definitive chemoradiation to a minimum of 66 Gy, with concurrent cisplatin (≥200 mg/m²) or carboplatin (≥AUC 9), for SCC of the oral cavity, oropharynx, or hypopharynx or larynx. Patients with base of tongue or tonsil cancer and ≤10 pack years of tobacco use, as well as those with nasopharynx, sinus or salivary gland cancer, are excluded. Adequate bone marrow, liver and kidney function is required. Prior therapy with investigational agents or EGFR inhibitors is not permitted. Randomization must take place within 16 weeks of the completion of chemoradiation with or without subsequent neck dissection. Patients are randomized 2:1 to afatinib 40 mg po qd or placebo, and treatment continues for 18 months in the absence of disease recurrence, second primary tumors, or intolerance to the study medication. Dose escalation to 50 mg qd is undertaken in patients with no side effects, and stepwise dose reduction to 30 or 20 mg po qd for diarrhea, skin toxicity or other adverse events is permitted. The primary endpoint is disease-free survival (DFS). The study is planned to accrue approximately 669 patients worldwide, with a 90% power to detect a hazard ratio of 0.72. Secondary endpoints are DFS at 2 years, overall survival, health-related quality of life, and safety.