Objectives/Hypothesis The effect of smoking and human papillomavirus (HPV) on overall survival (OS) of oropharyngeal squamous cell carcinoma (OPSCC) patients undergoing concurrent chemotherapy (CCRT) remains unclear. Study Design Retrospective review. Methods Clinical characteristics of OPSCC patients treated between 2008 and 2015 with CCRT were ed from medical records. OS curves and multivariate cox proportional hazard ratios (HRs) were examined. Results Of 120 evaluable patients, 71% had HPV+ tumors. Median follow‐up duration for the entire cohort was 41.5 months (range = 6–88 months). HPV+ current smokers experienced significantly worse 5‐year OS (73% alive vs. 36% alive, P = .01) and there was a similar trend in HPV− current smokers (66% alive vs. 31% alive, P = .28) compared to former/never smokers undergoing CCRT. In a multivariate cox proportional hazard model adjusted for age, gender, and overall tumor stage, HPV+ current smokers experienced nearly a fourfold increase in overall mortality in comparison to HPV+ never/former smokers (HR = 3.68, 95% CI = 1.35‐10.0). Similarly, current smokers with HPV− tumors (HR = 6.80, 95% CI = 1.11‐41.67) had increased mortality compared to never/former smokers. Conclusions Current smoking is associated with poor prognosis, independent of HPV status, in CCRT‐treated OPSCC patients. Current smoking produced an approximately four‐ to sevenfold increase in risk of mortality for HPV+ and HPV− patients, respectively. Regardless of pack years and HPV status, efforts should be made to achieve smoking cessation before CCRT. Level of Evidence 4. Laryngoscope, 126:2733–2738, 2016