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Summary Although several studies analyzed p53 and mismatch repair (MMR) gene expression separately in oral squamous cell carcinoma (SCC), no reports of combined assessment of both proteins in this cancer. The aim of this study was to investigate the roles of p53 and hMSH2 proteins in oral SCC as well as in oral dysplastic lesions (DL) in Yemen. Immunohistochemistry was used to examine the pattern of expression of p53 and hmsh2 proteins in 70 oral SCC and 21 oral DL obtained from Yemeni patients. p53 Immunoexpression was detected in 24 of the 70 oral SCC (34.3%) and 3 of 21 DL (14.3%) with no significant difference between the two groups. On the other hand, reduced expression of hMSH2 was detected in 26 of the 70 oral SCC (37.1%) and 2 of 21 oral DL (9.5%) with a statistically significant difference (P = 0.03). Both proteins were significantly related to the grade of tumor differentiation (P = 0.007 and 0.02, respectively). There was an inverse correlation between the levels of p53 and hMSH2 immunoexpression in the oral SCC (r = 0.42, P = 0.01). This study suggested that p53 may play a role in the early stages of oral carcinogenesis, while hMSH2 may be altered in the late stages. More importantly, the roles of p53 and hMSH2 in oral carcinogenesis seem to be interrelated in the pathogenetic pathway of oral SCC. Such a relationship has not been published previously in this type of cancer and needs to be clarified in future studies.