Oral medicine specialists rely upon accurate assessment of pathology to rationalise lesion management, especially for high-risk oral epithelial dysplasia, carcinoma in situ (CIS) and oral squamous cell carcinoma. Cross-discipline cancer research has highlighted the role of genetic instability in neoplasia. Improved diagnostic stringency from translation of immunostaining for DNA repair defects into current pathology practice has potential to benefit pathologists, clinicians and patients. The focus of this study was the obligatory and non-obligatory components of the MutLα and MutSα mismatch repair heterodimers, namely hMLH1, hMSH2, hPMS2 and hMSH6, which were studied in 274 formalin-fixed paraffin-embedded sections. A readily apparent inverse correlation between oral disease severity and both obligatory and non-obligatory components of MutLα and MutSα was observed (hMLH1, ρ=−0.715; hPMS2, ρ=−0.692; hMSH2, ρ=−0.728; and hMSH6, ρ=−0.702), with particularly conspicuous loss of hMSH6 expression from the stratum basale of CIS.