<p><strong>Background:</strong> Positive surgical margins in oral squamous cell carcinoma (OSCC) is an important predictor of recurrence. Unfortunately, recurrence is found in cases with negative surgical margins as well and hence molecular markers are being investigated to identify the tumor cells in negative surgical margins to improve the survival of patients. The study aimed to ascertain the prognostic role of p53, eIF4E and E-cadherin in negative surgical margins and association of their expression with clinical parameters, recurrence, and survival.</p><p><strong>Methods:</strong> India based retrospective cohort study of patients who were surgically treated for OSCC between 2011 and 2014. Thirty patients with negative surgical margins were assessed for this study. Sixty-four negative surgical margins were evaluated using immunohistochemistry with monoclonal mouse p53, monoclonal rabbit eIF4E and monoclonal mouse E-cadherin antibodies.</p><p><strong>Results:</strong> Fisher’s exact test, Fishers Freeman Halton exact test and contingency tables were used to assess the association between recurrence rate and clinicopathologic parameters also any association with the expression of p53, eIF4E and E-cadherin in the surgical margins and each patients’ clinical characteristics. ANOVA (analysis of variance) was used to assess the role of clinicopathologic parameters in survival of the patients. The sensitivity and specificity of each antibody along with positive and negative predictive values were calculated. Kaplan Meier was used for analysis of recurrence and five-year survival. P<0.05 was used to denote a statistically significant difference.</p><p><strong>Conclusion:</strong> This study could help in identification of patients with minimal residual cancer in the surgical margins and might help in better therapeutic management to improve survival of OSCC patients.</p>