Background: Studies have demonstrated better prognosis for patients (pts) with HPV-initiated OPC when compared to OPC caused by smoking. A small subset of pts however experience disease recurrence and have poor outcomes. We report our Cleveland Clinic experience with HPV-initiated OPC in an effort to identify determinants of a poor prognosis. Methods: We identified pts with stage III-IVb HPV-initiated OPC treated with definitive chemoradiotherapy between 2002 and 2012 from an IRB approved registry. HPV-initiated disease was determined by positivity for p16 by immunohistochemistry or HPV DNA by fluorescent in-situ hybridization. Radiation therapy was administered to a total dose of 70-74 Gy. Chemotherapy consisted of either cisplatin and 5-Fluorouracil, cisplatin or cetuximab. Kaplan-Meier estimates of disease-free survival (DFS) and overall survival (OS) were calculated. Univariate (UVA) and multivariate analyses (MVA) using Cox proportional hazards regression were performed to identify variables associated with inferior DFS and OS. Results: Of the 228 patients identified, 17% had T4 disease, 40% had N2c/3 disease, 51% had a smoking history (>10 pack years) while 31% were lifetime never smokers. Median follow up was 40 months. 3-year DFS and OS was 89% and 90% respectively. UVA revealed that DFS was inferior in pts with T4 (HR = 2.525; 95% CI = 1.089 to 5.848; P = 0.03) and N2c-N3 (HR = 2.364; 95% CI = 1.062 to 5.263; P = 0.04) disease. OS was also inferior in pts with T4 disease (HR = 2.123; 95% CI = 1.042 to 4.329; P = 0.04), and pts with a smoking history (HR = 2.475; 95% = CI 1.192 to 5.128; P = 0.02). On MVA, the most important predictors for an inferior DFS were smoking history, T4 and N2c-N3 disease. Patients with 2 or more of these risk factors had a significantly worse 3 –year DFS (77% vs. 94%; HR = 4.082; 95% CI = 1.828 - 9.091; P <0.001) and OS (83% vs. 93%, HR = 2.283; 95% CI = 1.193 - 4.367; P 0.01). Conclusions: Patients with HPV-initiated OPC and at least two high risk features, including T4, N2c/3, or >10 pack years of smoking, had significantly inferior DFS and OS. Such patients should not be considered for treatment de-intensification strategies.