AimThis study investigated the immunohistochemical expression of hMLH1 and hMSH2 proteins in lower lip squamous cell carcinoma (SCC) and actinic cheilitis (AC), to contribute to the understanding of the development of lower lip cancer.Methods and resultsForty cases of lower lip AC and SCC were studied. Quantitative immunohistochemical analysis was undertaken by counting 1000 cells (positive and negative) in each lesion. Statistical evaluation included Student's t‐test and one‐way anova. For SCC and AC, the mean number of hMLH1‐ and hMSH2‐positive cells decreased with advanced stage of the lesion. The largest mean number of immunostained cells was observed in AC cases without dysplasia or with mild dysplasia (hMLH1: 721.23 ± 88.116; hMHS2: 781.50 ± 156.93). Intermediate values were obtained for AC with moderate or severe dysplasia (hMLH1: 532.86 ± 197.72; hMHS2: 611.14 ± 172.48). Lower lip SSCs presented the smallest number of positive cells (hMLH1: 255.03 ± 199.47; hMHS2: 518.38 ± 265.68). A statistically significant difference was observed between groups (P < 0.001).ConclusionsThe results support the hypothesis that changes in the immunoexpression of these mismatch proteins are related to the process of carcinogenesis of the lower lip.