Objective: Our study aimed to characterize alteration in the immunohistochemical p16 expression in normal oral mucosa and non-neoplastic hyperproliferative disorders (i.e. frictional keratosis and mucosa from smokers). Study design: 43 specimen of oral mucosa were examined using immunohistochemistry. Results: In normal mucosa, there was strong positive nuclear staining in a proportion of fibroblasts and endothelial cells in the lamina propria, with variable expression in nuclei of the epithelial layer. However, when the patient?s tobacco smoking was examined, p16 nuclear staining in oral epithelium was seen in 4/20 (20%) of smokers and 0/23 (0%) of non-smokers. In every case of frictional keratosis (n=11), there was strong nuclear staining of some basal and supra-basal cells. In addition, there was strong nuclear staining of parakeratinizing squamous in a band above the spinous layer. In clinically normal oral epithelium of smokers and in frictional keratosis, basal and supra-basal cells expressed strong p16 nuclear staining which was absent in the control tissue examined. Conclusion: Our data suggest that p16 expression may be involved in the long-term loss of proliferation in cell senescence of oral mucosa.