Background: Neoadjuvant chemotherapy (NAC) followed by surgery (NAC + S) may enable treatment de-escalation in HPV-positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC). Objective: To evaluate oncologic outcomes and the potential to omit adjuvant therapy in patients undergoing NAC + S compared to upfront surgery. Methods: This retrospective study included 400 HPV+ OPSCC patients treated with surgery between 2005 and 2020. Of these, 121 received NAC prior to surgery, and 279 underwent upfront surgery. Clinical, pathological, and survival outcomes were compared. Propensity score matching (PSM) was used to adjust for baseline differences. Results: The NAC group had higher negative margin rates (78.5% vs. 68.8%) and lower rates of lymphovascular invasion (19.0% vs. 34.0%) and extranodal extension (25.6% vs. 47.7%). Adjuvant therapy was less frequent in the NAC group (59.5% vs. 78.1%). After PSM, 5-year recurrence-free and disease-specific survival did not differ significantly. Among 62 NAC patients with no adverse pathological features, 43 omitted adjuvant therapy and remained disease-free. Conclusion: NAC + S achieved comparable survival outcomes to upfront surgery and allowed omission of adjuvant therapy in selected patients, supporting its role in treatment de-intensification for HPV+ OPSCC.