Head and neck cancer have high local recurrence rates when tumour resection is incomplete. The choice of management if a margin is positive or close is wider surgical resection. We postulate that genetic changes precede gross histological alterations; hence use of molecular markers (4E and P53) to establish surgical margins may decrease the local recurrence and improve clinical outcomes. We studied E4 and P53 at the margins of resected mucosal lesions of the oro-pharynx of lesions reported employing histopathology alone at the RDH from March 2005 to March 2009. These results were co-related with the clinical outcomes of these patients, ensuring a minimum follow up of 2 years, and an assessment made of the effectiveness of the two immunohistochemical markers. We also compare the efficacy of E4 and P53 as predictors of negative prognosis.