IMPORTANCE Little is known about treatment outcomes for T4 oropharyngeal squamous cell carcinoma (OPSCC), particularly in the era of human papillomavirus (HPV)-related disease. OBJECTIVE To evaluate oncologic outcomes for T4 OPSCC treated with primary surgical and nonsurgical therapies. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of 131 patients from a single academic hospital, who were treated for T4a or T4b OPSCC (with any N stage and without distant metastatic disease at presentation) between 1998 and 2012 and had a minimum 2-year follow-up (the median follow-up time was 34.6 months). This study was conducted between January 1, 1998, and November 1, 2012. INTERVENTIONS Sixty-nine patients underwent nonsurgical therapy, 47 (68%) of whom had p16-positive tumors. Nonsurgical treatment paradigms included induction chemotherapy followed by chemoradiotherapy (n = 36 [54%]), concurrent chemoradiotherapy (n = 29 [43%]), and induction chemotherapy followed by radiation therapy alone (n = 2 [3%]). Sixty-two patients underwent surgical treatment, 50 (81%) of whom had p16-positive tumors. Fifty-seven surgical patients (92%) received adjuvant therapy. MAIN OUTCOMES AND MEASURES Overall survival (OS)was the primary outcome measure. Secondary outcome measures included disease-specific survival (DSS), disease-free survival (DFS), 2-year gastrostomy and tracheostomy tube rates, and major complication rates. RESULTS Significant baseline differences between the surgical vs nonsurgical groups included age (mean 59.8 vs 55.4 years [P =.005]), sex (male, 95%vs 84%[P =.04]), body mass index (<18.5 [calculated as weight in kilograms divided by height in meters squared], 3%vs 16% [P =.02]), and smoking history of 10 or more pack-years (48%vs 77%[P =.003]). For p16-positive patients, Kaplan-Meier estimates of OS, DSS, and DFS were significantly higher for surgically treated patients than for the nonsurgical group (χ2 1 = 7.335 for log-rank P =.007, χ12 1 = 8.607 for log-rank P =.003, and χ12 = 7.763 for log-rank P =.005, respectively). For p16-negative patients, Kaplan-Meier estimates of OS and DSS were higher for the surgical group but did not reach statistical significance (χ12 = 2.649 for log-rank P =.10 and χ12 = 2.077 for log-rank P =.15, respectively), while estimates of DFS were significantly higher for patients treated with primary surgery (χ12 = 3.869 for log-rank P =.049. In a multivariable Cox survival analysis, p16-positive immunohistochemical status had a significant positive association with OS (hazard ratio [HR], 0.55; 95%CI, 0.32-0.95 [P =.03]), DSS (HR, 0.45; 95%CI, 0.22-0.92 [P =.03]), and DFS (HR, 0.55; 95%CI, 0.32-0.95 [P =.03]), and nonsurgical treatment had a significant negative association with OS (HR, 2.79; 95%CI, 1.51-5.16 [P =.001]), DSS (HR, 3.38; 95%CI, 1.59-7.16 [P =.002]), and DFS (HR, 2.59; 95%CI, 1.51-4.45 [P =.001]). CONCLUSIONS AND RELEVANCE Primary surgical treatment may be associated with improved outcomes in patients with T4 OPSCC. p16 Immunohistochemical status remains a strong prognostic indicator even in patients with locally advanced disease.