ImportanceCardiovascular events are an important cause of morbidity in patients with oropharyngeal squamous cell carcinoma (OPSCC). Radiation and chemotherapy have been associated with increased risk of stroke; up-front surgery allows the opportunity for (chemo)radiotherapy de-escalation.ObjectiveTo evaluate whether up-front surgery was associated with decreased stroke risk compared to nonsurgical treatment for OPSCC.Design, Setting, and ParticipantsThis cohort study was conducted at the US Veterans Health Administration and examined US veterans diagnosed with nonmetastatic OPSCC from 2000 to 2020. Data cutoff was September 17, 2021, and data analysis was performed from October 2021 to February 2022.ExposuresUp-front surgical treatment or definitive (chemo)radiotherapy as captured in cancer registry.Main Outcomes and MeasuresCumulative incidence of stroke, accounting for death as a competing risk; and association between up-front surgery and stroke risk. After generating propensity scores for the probability of receiving surgical treatment and using inverse probability weighting (IPW) to construct balanced pseudo-populations, Cox regression was used to estimate a cause-specific hazard ratio (csHR) of stroke associated with surgical vs nonsurgical treatment.ResultsOf 10 436 patients, median (IQR) age was 61 (56-67) years; 10 329 (99%) were male; 1319 (13%) were Black, and 7823 (75%) were White; 2717 received up-front surgery, and 7719 received nonsurgical therapy with definitive (chemo)radiotherapy. The 10-year cumulative incidence of stroke was 12.5% (95% CI, 11.8%-13.3%) and death was 57.3% (95% CI, 56.2%-58.4%). Surgical patients who also received (chemo)radiotherapy had shorter radiation and chemotherapy courses than nonsurgical patients. After propensity score and IPW, the csHR of stroke for surgical treatment was 0.77 (95% CI, 0.66-0.91). This association was consistent across subgroups defined by age and baseline cardiovascular risk factors.Conclusions and RelevanceIn this cohort study, up-front surgical treatment was associated with a 23% reduced risk of stroke compared with definitive (chemo)radiotherapy. These findings present an important additional risk-benefit consideration to factor into treatment decisions and patient counseling and should motivate future studies to examine cardiovascular events in this high-risk population.