BACKGROUND: Analysis of the impact of risk factors on survival in patients with oropharyngeal squamous cell carcinoma (OPSCC) treated by primary intensity-modulated radiotherapy (IMRT). METHODS: One hundred forty patients were included with tissue microarray (TMA) construction and immunohistochemical analysis in 124 patients (87%). RESULTS: Survival analysis of patients classified into 3 risk categories according to an algorithm based on p16, smoking, T classification, and N classification revealed significant differences with a low, intermediate, and high-risk group. There was a significant impact of p53 expression as surrogate marker for smoking on outcome. In multivariate analysis, p16-positivity was a positive predictor and alcohol as well as N classification was a negative predictor for survival. The algorithm was modified based on alcohol instead of smoking with even more significant differences between the groups. CONCLUSIONS: A risk model based on multiple factors instead of p16 as single marker can define different risk groups to select patients for treatment deintensification in future prospective clinical trials. © 2013 Wiley Periodicals, Inc. Head Neck, 2013.