Importance: The optimal treatment strategy for patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) of the base of the tongue (BOT) has not been sufficiently studied. Objective: To investigate the rate of and risk factors for occult contralateral nodal disease in patients with HPV-related BOT OPSCC undergoing transoral surgery and bilateral neck dissections. Design, Setting, and Participants: This retrospective case series reviewed the medical records of patients with HPV-related BOT OPSCC who underwent transoral surgery and bilateral neck dissections from January 1, 2002, through December 31, 2018, at the tertiary care center of Washington University School of Medicine in St Louis. Patients had a median follow-up of 30.0 months (interquartile range, 11.0-60.4 months). Patients with recurrent disease or multiple synchronous OPSCC primary tumors were excluded for a total of 89 patients. Data were analyzed from January 1 through June 1, 2019. Main Outcomes and Measures: The primary outcome was the rate of contralateral occult nodal disease. Secondary outcomes were potential risk factors for contralateral occult nodal disease and regional recurrence rates. Results: Eighty-nine patients were included in the series, of whom 81 (91.0%) were men. The mean (SD) age was 60 (9) years. Overall, 34 patients (38.2%) had pathologic contralateral nodal metastases. Seventy patients had no clinical evidence of contralateral nodal disease. Of these 70, occult nodes were identified in 15 (21.4%). Risk of contralateral disease was higher when the primary tumor crossed midline (odds ratio, 6.23; 95% CI, 1.71-22.77). Of the 55 patients with no occult disease identified, only 2 (3.6%) received radiotherapy to the contralateral neck, and no regional recurrence of disease was noted. Conclusions and Relevance: Given the rate of occult contralateral nodal disease of 21.4%, it appears that contralateral elective neck dissection or radiotherapy should be recommended in patients with HPV-related BOT OPSCC. Patients with a pathologically negative result of contralateral neck dissection may not benefit from radiotherapy to that nodal basin. Future prospective investigations should evaluate functional and oncologic outcomes of contralateral elective neck dissection compared with elective radiotherapy in the contralateral neck for HPV-related BOT OPSCC.