Local and regional recurrence is the principal reason for treatment failure in squamous cell carcinoma (SCC) of the head and neck. The conventional method of evaluating surgical margins for cellular atypia does not always predict risk of local recurrence accurately. Immunostaining of surgical margins for tumor markers may provide a more precise evaluation of risk of local recurrence. Paraffin-embedded tissue blocks of surgical margins from 24 patients with oral cavity and oropharyngeal squamous cell carcinoma were immunostained for p53 protein. Fifty-eight percent of the patients had at least one margin stain positive for p53, including eight of ten patients whose SCC recurred locally. The sample odds ratio test predicted a 5.333 times higher chance of local recurrence with at least one p53 positive surgical margin. The implications of these results for patient management and further investigations will be discussed.