We performed a retrospective study to compare clinical outcomes among 51 consecutively presenting patients-38 men and 13 women, aged 46 to 74 years (median: 57)-with locally advanced human papillomavirus (HPV)-negative oropharyngeal cancer who were treated with either primary surgery followed by postoperative radiotherapy (S/RT group; n = 22) or definitive chemoradiotherapy alone (CRT group; n = 29). Within the cohort, 45 patients reported a history of tobacco use, with a median intensity of 40 pack-years. In addition, 39 patients (76%) reported moderate to heavy alcohol use. At baseline, there were no statistically significant differences between the two cohorts in sex, median age, cancer stage, intensity of smoking history, and alcohol use (p > 0.05 for all). Radiation doses ranged from 40 to 70 Gy (median: 70). Follow-up ranged from 2 to 93 months (median: 29). After treatment, we found no difference between the S/RT group and the CRT group in the incidence of locoregional recurrence (36 vs. 24%; p = 0.43) or distant metastases (14 vs. 21%; p = 0.56). Likewise, the difference in 2-year estimates of progression-free survival in the two groups was not significant (66 vs. 62%; p = 0.64), nor was the difference in 2-year overall survival (75 vs. 76%; p = 0.83). We conclude that treatment with either (1) primary surgery followed by postoperative radiotherapy or (2) CRT for locally advanced HPV-negative oropharyngeal cancer results in similar outcomes. In view of the relatively poor prognosis for patients with HPV-negative disease compared with their HPV-positive counterparts, clinical trials to investigate intensifying treatment may be warranted.