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Human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) has shown resistance to conventional concurrent chemoradiation (CRT) therapy and carries a relatively poor prognosis in comparison with HPV-positive disease, with decreased locoregional control and overall survival (OS). In the present analysis, we examine whether upfront surgical resection improves overall survival in a large national sample.To compare survival outcomes among patients with newly diagnosed cT1-2 N1-2b HPV-negative OPSCC when treated with primary surgical resection vs CRT.This was an observational study of factors associated with primary treatment modality were identified using multivariable logistic regression. Overall survival was compared using Kaplan-Meier analysis with log-rank tests, multivariable Cox regression, and propensity score matching. Statistical tests were 2-sided. Patients newly diagnosed as having cT1-2 N1-2b pathologically confirmed HPV-negative OPSCC in 2010 to 2012 were identified using the National Cancer Data Base, which includes more than 70% of patients newly diagnosed as having cancer in the United States.Primary surgical resection vs definitive CRT.Overall survival.We identified 1044 patients, among whom 460 (44.1%) received upfront surgery and 584 (55.9%) received CRT. Median age was 59 years (range, 25-90 years); 812 patients were male (77.8%), 232 were female (22.2%). Median follow-up was 30 months. Approximately 59% of surgical patients received adjuvant CRT. On multivariable Cox regression, upfront surgery was not associated with increased OS when compared with CRT (adjusted hazard ratio [HR], 1.01; 95% CI, 0.74-1.39; P = .93). Propensity score-matching identified a cohort of 822 patients and redemonstrated equivalent OS (HR, 1.14; 95% CI, 0.81-1.62; P = .46). Lack of OS benefit with upfront surgery persisted in a subset analysis of patients with margin-negative resection (HR, 0.97; 95% CI, 0.66-1.45; P = .88).In this observational study, OS was similar for patients with HPV-negative OPSCC when treated with primary surgery vs CRT. Most surgical patients received trimodal therapy with adjuvant CRT. Our data may have implications for future research focusing on optimal patient selection for surgery.