Background: The clinical outcome of patients (pts) with resected HNSCC at high risk of recurrence remains poor. Disease free survival (DFS) at 5 years is around 40% after standard adjuvant chemoradiation (CRT). The use of anti-EGFR monoclonal antibodies combined with radiotherapy was shown to be effective in pts with HNSCC, and combination with CRT showed to be safe. Methods: This open-label phase III randomized trial will investigate whether the addition of the anti-EGFR antibody panitumumab to adjuvant CRT significantly prolongs DFS in HNSCC at high risk of recurrence. Pts with high-risk HNSCC, due to the presence of close resection margins (<5 mm) or extracapsular extension, will be randomized to receive 7 weeks of concomitant CRT (three cycles of cisplatin or two cycles of cisplatin and 5-fluorouracil with 66 Gy radiotherapy), +/- weekly panitumumab 2.5 mg/kg. Both IMRT and 3D-RT are allowed in the study, the use of simultaneous integrated boost technique is mandatory. The protocol includes an extensive quality assurance program for radiotherapy. The primary study endpoint is DFS. The study is powered to 80% for showing a 10% increase in 5-year DFS, from 36% to 46% (corresponding to a hazard ratio 0.76) at the 2-sided 5% significance level. Hence, 800 pts must be randomized over 5 years. A restricted cohort of pts participating in the study will also receive a single dose of panitumumab prior to surgery. The aim of this sub-study is to test the predictive potential of a gene expression classifier to identify a subgroup of pts most likely to benefit from the experimental treatment. Two correlative studies are part of the trial, which will investigate the predictive role of biologic assays (lymphocyte apoptosis test and SNPs analysis) and pt/treatment-related parameters on the development of late radiation-induced side effects, and the relationship between treatment toxicity and quality of life. Biomarker evaluation will be performed on tissue and serum samples collected from all consenting pts. The trial opened to recruitment in January 2011.