The effectiveness of postoperative radiotherapy (PORT) in improving outcomes remains debatable for oral squamous cell carcinoma (OSCC) patients with pathological intermediate-risk factors (IRFs) after surgery. A retrospective analysis was conducted on 432 intermediate-risk OSCC patients defined by histological reporting of close margin (<5 mm), early nodal disease (pN1), depth of invasion/tumour thickness ≥5 mm, perineural invasion, and/or lymphovascular invasion. Outcomes measured were disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). PORT was associated with an improvement in 5-year DFS on univariable analysis (80% vs 71%; P = 0.044), but this did not remain significant on multivariable analysis. PORT was not associated with differences in DSS or OS. The surgical salvage rate was similar in the PORT and surgery-only groups (41% vs 47%; P = 0.972). Perineural invasion was found to be an independent predictor of inferior DSS (hazard ratio (HR) 2.19), DFS (HR 1.89), and OS (HR 1.97). Significantly worse outcomes were observed for patients with ≥4 concurrent IRFs. The application of PORT was associated with lower rates of recurrence, but the benefit was less apparent on mortality. Patients with perineural invasion and multiple concurrent IRFs were found to be at greatest risk, representing a subset of intermediate-risk OSCC patients who may benefit from PORT.