Background: The role of adjuvant radiotherapy (RT) in early-stage oral cavity squamous cell carcinoma (OCSCC) following adequate surgery remains uncertain. The phase III AREST trial (NCT03853655) randomized such patients to observation (OBS) versus RT. We analyzed outcomes in patients who were screen failures but met trial eligibility criteria. Methods: Patients with pT1–T2, N0 (AJCC 8th edition) OCSCC with depth of invasion (DOI) 5–10 mm who underwent margin-negative resection and neck dissection were included. Patients with second primaries or no follow-up were excluded. The primary endpoint was locoregional control (LRC); secondary endpoints included disease-free survival (DFS) and overall survival (OS). Results: A total of 276 patients were analyzed. The primary reasons for screen failure were patient refusal (74.3%) and physician decision (18.8%). Tumor subsites included tongue (63%) and bucco-alveolar complex (37%). Eighty-five patients (30.8%) received RT, while 191 (69.2%) underwent OBS. The RT cohort had significantly higher-risk features, including perineural invasion (44% vs 13%, p<0.001), DOI 8–10 mm (61% vs 21%, p<0.001), and WPOI type 5 (21% vs 12%, p=0.042). Physician-driven screen failure was more common in the RT group (44% vs 8%). At a median follow-up of 42 months, 3-year LRC was 87.0% (95% CI: 76.2–93.2) in RT versus 83.4% (95% CI: 77.1–88.1) in OBS (p=0.795). Corresponding 3-year DFS was 78.3% vs 81.9% (p=0.537), and OS was 81.6% vs 87.2% (p=0.421). On multivariable analysis, adjuvant RT was not associated with a statistically significant improvement in outcomes: LRC (HR 0.57; p=0.152), DFS (HR 0.72; p=0.326), and OS (HR 0.62; p=0.215). Conclusions: Despite enrichment for adverse pathological features, patients receiving RT demonstrated outcomes comparable to OBS. These findings suggest that adjuvant RT may mitigate the adverse impact of high-risk pathological features, supporting its consideration in selected patients with early-stage OCSCC.