Background: Masticator space involvement in oral cavity squamous cell carcinoma (OCSCC) is considered an unresectable disease. Nevertheless, achieving negative resection margins is feasible in limited masticatory space involvement. Materials and Methods: A multi-institutional study on OCSCC patients with masticator space invasion who underwent surgical resection. Margin status was assessed according to anatomic tumor involvement of the inframandibular and supra-mandibular notch. Results: One-hundred and thirty-two patients met the inclusion criteria. Then, 67 patients (50.8%) were diagnosed with a supra-notch tumor and 65 (49.2%) with an infra-notch disease. Negative margins were more common in the infra-notch group (43.3 vs. 23.1%, p = 0.014), and positive margins were more common in the supra-notch group (41.5 vs. 23.9%, p = 0.041). Multivariable analysis demonstrated that supra-notch tumors had an increased likelihood for involved resection margins (odds ratio = 2.46, p = 0.036). Conclusion: OCSCC patients with masticator space involvement are prone for positive surgical margins in tumors extending above the supra-mandibular notch.