In this study, a possible association was examined between the immunoexpressions of p53, cyclin D1, Ki-67 and tobacco exposure and the risk of oral cancer (OC) in premalignant and malignant formalin-fixed, paraffin-embedded oral mucosal tissue specimens from patients from Yemen (n=24, all were pre-malignant) and India (n=16, 11 were OCs). Overexpressions of p53, cyclin D1 and Ki-67 were found in 100%, 45.5% and 80% of the OCs, compared to 65.5%, 82.8% and 85.1% of the pre-malignant lesions, respectively. In the pre-malignant lesions, a statistically significant correlation was found between histopathological grading and expressions of cyclin D1 (p = 0.001) and Ki-67 (p = 0.03), and between anatomical site and expression of Ki-67 (p = 0.01). Coexpressions of the three proteins in the cases examined was found to correlate significantly to each other (cyclin D1: p53, r = 0.48, p = 0.002; p53: Ki-67, r = 0.41, p = 0.008) except for cyclin D1: Ki-67. These findings suggest that the expressions of p53, cyclin D1 and Ki-67 might contribute to OC susceptibility in oral mucosal lesions examined from Yemen and India. The importance of the three proteins examined as biomarkers in OC and pre-malignant lesions deserves particular attention because it might offer further understanding of the development of these lesions, particularly in populations heavily exposed to tobacco habits. Abnormalities of both cyclin D1 and Ki-67 might play an important role in the development of oral pre-malignant lesions and warrant further studies. Larger studies are, therefore, necessary in the two countries to examine the role of these biomarkers in OCs and premalignant oral mucosal lesions.