Introduction: The World Health Organization (WHO)points out the following lesions as the main oral potentially malignant disorders: leukoplakia, erythroplakia, actinic cheilitis, oral submucous fibrosis and lichen planus. Oral Cancer accounts for approximately 3% of all malignancies and found in 270,000 patients annually worldwide. Aims: To study the expression of SMAD-4 in oral potentially malignant disorders and oral squamous cell carcinoma and its role as a prognostic marker. Materials & Methods: 20 specimens of OPMD, 20 OSCC and10 of normal mucosa were taken. They were stained with standard H&E and IHC using primary antibody SMAD 1. Expression of SMAD-4 protein was determined by staining quantitative assessment of the percentage of marked tumor cells. Group comparisons were made with the Chi-Sq test as data was skewed so comparisons for two groups were made by Mann-Whitney test. Correlations between scores were calculated with Spearman correlation coefficient. All statistical tests were two-sided and performed at a significance level of α=.05. Analysis was conducted using IBM SPSS STATISTICS (version 22.0). Results: On comparing the staining intensities of group 1 (OPMD) and group 2 (OSCC) statistically highly significant difference is obtained (p value=.001) and on comparison of percentages of immunopositive cells of group 1 (OPMD) and group 2 (OSCC) statistically highly significant difference is obtained (p value=.029). Conclusion: SMAD-4 was a tumor suppressor and loss of SMAD-4 expression may lead to spontaneous oral squamous cell carcinoma development, patients whose oral potentially malignant lesions with higher levels of SMAD-expression displayed a significantly higher rate of malignant transformation.