Background: With the rise of oropharyngeal squamous cell carcinoma associated with human papillomavirus (HPV), appropriate treatment strategies continue to be tailored toward minimizing treatment while preserving oncologic outcomes. This study aimed to compare the outcomes for those undergoing transoral resection with or without adjuvant therapy for HPV-related oropharyngeal carcinoma. Methods: A case-match cohort analysis was performed at two institutions on patients with HPV-related oropharyngeal squamous cell carcinoma. All the subjects underwent transoral surgery and neck dissection. The patients treated with surgery alone were matched 1:1 to those treated with surgery and adjuvant therapy using two groups identified as confounders: T-stage (T1/2 or T3/4) and number of pathologically positive lymph nodes (≤4 or >4). Results: The study identified 105 matched pairs, with a median follow-up period of 42 months (range 3.1–102.3 months). The patients were staged as T1/T2 (86%) or T3/4 (14%). Each group had five patients with more than four positive lymph nodes. Adjuvant therapy significantly improved disease-free survival (hazard ratio [HR] 0.067; 95% confidence interval [CI] 0.01–0.62) and was associated with a lower risk of local and regional recurrence (risk ratio [RR] 0.096; 95% CI 0.02–0.47). No difference in disease-specific survival (HR 0.22; 95% CI 0.02–2.57) or overall survival (HR 0.18; 95% CI 0.01–2.4) was observed with the addition of adjuvant therapy. The risk of the gastrostomy tube was higher for those receiving adjuvant therapy (RR 7.3; 95% CI 2.6–20.6). Conclusions: Transoral surgery is an effective approach for the treatment of HPV-related oropharyngeal carcinoma. The addition of adjuvant therapy appears to decrease the risk of recurrence and improve disease-free survival but may not significantly improve overall survival.