IMPORTANCE: Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has a favorable prognosis, and p16 immunohistochemistry is a surrogate marker of high-risk HPV infection and strong prognosticator. Given this favorable prognosis, treatment de-escalation for p16-positive OPSCC is now being considered with the goal of decreasing treatment-associated morbidity without compromising tumor control. The role of adjuvant chemotherapy in this setting is becoming increasingly unclear. OBJECTIVE: To compare survival between surgically managed patients with p16-positive OPSCC who received adjuvant chemoradiotherapy and patients who received adjuvant radiotherapy alone. DESIGN, SETTING, AND PARTICIPANTS: This was a cohort study of patients with OPSCC diagnosed from June 1996 to June 2010, with follow-up through December 2014, at a single tertiary referral center. One hundred ninety-five surgically managed, p16-positive patients without a history of head and neck cancer or distant metastasis at time of diagnosis were included. EXPOSURES: Patients were dichotomized into adjuvant radiotherapy and adjuvant chemoradiotherapy groups. MAIN OUTCOMES AND MEASURES: Overall survival was the primary outcome, and disease-free survival was the secondary outcome. Propensity-weighted multivariate Cox proportional hazards analysis was conducted to quantify the effect of adjuvant chemotherapy on survival. RESULTS The study included 195 patients with p16-positive, surgically managed OPSCC. Median duration of follow-up was 87 months (interquartile range, 68-116 months). Ninety patients received adjunct chemoradiotherapy (mean age, 54.3 years), 88 patients received adjuvant radiotherapy (mean age, 56.4 years), and 17 patients received surgery alone. The 5-year overall survival rate for patients who received adjuvant chemoradiotherapy was 82% (95% CI, 73%-90%) and 84% (95% CI, 76%-91%) for patients who received adjuvant radiotherapy alone. The 5-year disease-free survival rate for patients who received adjuvant chemoradiotherapy was 79% (95% CI, 71%-88%) and 79% (95% CI, 70%-88%) for patients who received radiotherapy alone. After weighting cases by the inverse probability of receiving adjuvant chemotherapy and controlling for age, comorbidity, smoking, pathological T stage, and pathological N stage, the receipt of adjuvant chemotherapy was not significantly associated with disease-free survival (adjusted hazard ratio, 0.91; 95% CI, 0.59-1.42) but was associated with a statistically insignificant yet clinically meaningful increase in all-cause mortality (adjusted hazard ratio, 1.46; 95% CI, 0.91-2.33). CONCLUSIONS AND RELEVANCE: Among patients with p16-positive OPSCC managed surgically with adjuvant radiotherapy, the addition of adjuvant chemotherapy provided no additional disease-free survival benefit and was associated with worse overall survival. These results should help inform future clinical trials aiming to deescalate treatment for p16-positive patients.