Background: Evidence regarding the prognostic value of perineural invasion (PNI) in oral squamous cell carcinoma (OSCC) and whether PNI alone warrants consideration of adjuvant therapy is controversial. We evaluated whether histopathological sub-categorization of PNI improves risk stratification. Methods: PNI was evaluated for nerve size, number of foci, and distance from the tumor in 318 OSCC patients. Univariable and multivariable analyses were performed, with local failure (LF) and disease-specific survival (DSS) as the primary endpoints. Results: PNI did not influence prognosis when classified as absent versus present. In contrast, multifocal PNI was associated with LF (P=0.049) and decreased DSS (P=0.043) on multivariable analyses. The size of the involved nerve separated those with multifocal PNI into intermediate (<1 mm) and high-risk (≥1 mm) groups. Unifocal PNI and distance from the tumor did not influence prognosis. Multifocal PNI was associated with worse prognosis irrespective of post-operative radiotherapy (PORT). Conclusions: Multifocal PNI is associated with poor outcomes even with PORT suggesting consideration of therapeutic escalation, particularly with involved nerves ≥1 mm. Unifocal PNI did not affect prognosis even in the absence of PORT, which may not be required if this is the sole risk factor. Prospective validation and testing of these hypotheses is essential before implementation.