Background: Definitive concurrent chemoradiation (CRT) is a standard treatment for patients (pts) with squamous cell carcinoma of the oropharynx (SCCOPx). We compared the outcomes and toxicity of high-dose cisplatin (HDC) versus weekly (WC) definitive CRT for patients with HPV-related SCCOPx. Methods: All pts with p16 positive SCCOPx treated with definitive CRT with cisplatin between 2010 and 2014 at a single institution were reviewed. CTCAE v 4.03 toxicity criteria was used. The Kaplan-Meier method was used to estimate event-free survival (EFS) and the overall survival (OS). Results: Of the55 pts included, 85% were males and 57% had a history of smoking > 10 pack-years. Median age at diagnosis was 55.4 years (40.3-80.0 years). 22 pts were treated with HDC at doses of 100 mg/m2 on days 1 and 22; 33 were treated with WC at 40 mg/m². Groups were well balanced in respect to sex (p = 0.454) and smoking history (p = 0.799). The median total dose of cisplatin was 200 mg/m2 for both cohorts, with a mean of 195 mg/m2 for the HDC group and 189 mg/m2 for the WC group. At median follow-up of 27 months, there was one local failure and no distant failures in the HDC cohort. In the WC group, there were 6 total failures (2 local and 4 distant). Estimated 2-year EFS was better in HDC cohort as compared to WC (96% vs. 75%; p = 0.05), despite a longer follow-up in pts with HDC (32 months vs. 19 months). There was no significant difference in 2-year OS (95% vs. 94%; p = 0.4). In terms of toxicity, weight loss was marginally higher in the HDC arm compared to WC arm; all weight loss grades (100% vs 87%, p = 0.12) and weight loss > grade 1 (77% vs 60%; p = 0.19). However, gastric tube dependence at six months following therapy was similar (13% vs. 12%, p = 1.0). Acute renal injury of any grade was higher in HDC group (55% vs. 36%, p = 0.18) but grade 3 or 4 hematological toxicity was similar (20% vs 23%, p = 0.76). Conclusions: HPV-positive SCCOPx treated with definitive CRT with either HDC or WC had similar toxicity profile for several parameters. HDC has better EFS when compared with WC and this seems to be driven by increased distant failure rates, although the OS was similar. A longer follow-up will be needed to better assess if the OS remains similar.