Importance: Regional lymph node metastasis remains an important prognostic factor in patients with oropharyngeal squamous cell carcinoma (OPSCC). Although survival among patients with regional metastasis in human papillomavirus (HPV)-related OPSCC is more favorable compared with patients who are HPV negative, prognostic variables associated with failure in patients with single-node metastasis are not known. Objective: To evaluate recurrence and survival in patients with HPV-related OPSCC with single-lymph node metastasis treated with transoral surgery. Design, Setting, and Participants: A retrospective cohort study was conducted of 207 adults with newly diagnosed p16-positive OPSCC and pathology-confirmed single-node disease who underwent surgical resection with or without adjuvant therapy at 2 tertiary academic medical centers from January 1, 2007, to December 31, 2016. Statistical analysis was performed from September 1, 2018, to September 1, 2020. Interventions: Surgery alone (n = 59), surgery with adjuvant radiation (n = 75), or surgery with adjuvant chemoradiation (n = 73). Main Outcomes and Measures: The primary outcome was regional recurrence. Secondary outcomes included overall survival, any recurrence, and identification of factors associated with regional recurrence and overall survival. Results: Among 207 patients, 178 (86%) were men, with a median age of 57 years (range, 35-82 years) at the time of surgery. Median follow-up was 36.2 months (range, 7-127 months). Regional recurrence occurred in 11 patients (5%). Of these, 1 patient (9%) was lost to follow-up after diagnosis, 1 (9%) was treated with palliative chemotherapy, and 9 (82%) were treated with curative intent. Ultimately, 7 patients received successful salvage treatment, and 3 died with disease. Overall, there were 21 patients (10%) with any recurrence, with 4 patients (19%) experiencing local recurrence, 11 (52%) experiencing regional recurrence, and 6 (29%) experiencing distant metastasis. The 5-year overall survival was 95% (95% CI, 89%-98%) for all patients. Older age (odds ratio [OR], 1.2; 95% CI, 1.1-1.2), advanced T stage (OR, 3.5; 95% CI, 0.9-14.0), and positive margins (OR, 10.9; 95% CI, 1.8-67.5) were associated with increased regional recurrence. Extranodal extension (OR, 0.2; 95% CI, 0.04-0.8), lymph node size greater than 3 cm (OR, 0.2; 95% CI, 0.1-0.7), and adjuvant therapy (OR, 0.08; 95% CI, 0.02-0.4) were associated with decreased regional recurrence. Advanced comorbidities (hazard ratio, 6.20; 95% CI, 1.4-27.7), lymphovascular invasion (hazard ratio, 4.7; 95% CI, 1.0-21.2), and regional recurrence (hazard ratio, 16.0; 95% CI, 3.1-82.0) were associated with worse overall survival. Conclusions and Relevance: The findings of this cohort study suggest that patients with HPV-related OPSCC and single-node disease undergoing surgical resection with or without adjuvant treatment have excellent survival. Adjuvant therapy appears to improve regional control. Among patients with regional recurrence of OPSCC, there is a high rate of successful salvage treatment..