Aims To evaluate whether response-adapted surgical margin de-escalation following neoadjuvant chemotherapy (NACT) compromises oncologic outcomes in oral cavity squamous cell carcinoma (OCSCC). Methodology A retrospective cohort study of OCSCC patients treated with NACT, surgery, and adjuvant radiotherapy was performed. Patients were stratified into radical-margin (≤December 2021) and conservative-margin (≥January 2022) cohorts. Clinicopathologic variables, margin status, recurrence patterns, and disease-free survival (DFS) were analyzed. Multivariable Cox regression identified independent predictors. Propensity score matching (PSM) using pre-treatment clinical variables minimized baseline imbalance. Results A total of 130 patients were included (radical: n=59; conservative: n=71). Rates of positive (3.0% vs 1.9%) and close margins (7.5% vs 7.5%) were comparable. The conservative cohort demonstrated lower recurrence (18.3% vs 32.2%) and fewer distant metastases (8.5% vs 22.0%). On multivariable analysis, margin de-escalation was not associated with inferior DFS and independently predicted improved DFS (HR 0.44, p=0.016). Extranodal extension predicted worse DFS (HR 2.82, p=0.003). PSM (31 matched pairs) confirmed no DFS disadvantage. Conclusion Response-adapted margin de-escalation following NACT is oncologically safe and supports a tailored surgical approach in OCSCC without compromising outcomes. Conflict of Interest No conflicts of interest to declare