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Objectives This study explored the expression of DNA mismatch repair (MMR) proteins in a range of oral biopsies. We further evaluated the significance of MMR protein expression combined with basic demographic data in differentiating grades of oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC). Study Design Immunohistochemical expression of MutSα (hMLH1 and hPMS2) and MutLα (hMSH2 and hMSH6) were compared in 98 formalin-fixed paraffin embedded oral biopsies: 21 normal, 24 mild-dysplasia (MD), 8 moderate-to-severe-dysplasia (SD), and 45 OSCC. Results Expression of hMLH1, hPMS2, and hMSH2 was reduced in MD, SD, and OSCC compared with the normal. Reduced hMSH2 immunoreactivity discriminated poorly differentiated OSCC from well-differentiated OSCC. The diagnostic model correctly classified 71.4% of cases and revealed that hPMS2-negative biopsies were more likely to be cancerous (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.000-0.813; P = .040). Conclusion The results suggested a diagnostic role for MMR proteins in OED and OSCC. [ABSTRACT FROM AUTHOR]