Objective: Nowadays, much attention has been focused on the search for new non-invasive methodologies able to predict malignant transformation of oral mucosa cells. The aim of the present study was to comparatively evaluate DNA damage (micronucleus) and cellular death (pyknosis, karyolysis and karyorrhexis) in exfoliated oral mucosa cells from smokers and non-smokers in buccal mucosa cells. Study Design: A total of 24 young, healthy smokers and 14 non-smokers were included in this setting. Individuals had epithelial cells from the cheek mechanically exfoliated, placed in fixative and dropped in clean slides which were checked for the above nuclear phenotypes. Results: Smokers presented more (p < 0.05) micronucleated oral mucosa cells than non-smokers. Tobacco smoke was not able to increase other nuclear alterations closely related to cytotoxicity such as karyorrhexis, pyknosis and karyolysis. Conclusion: In summary, these data indicate that the cigarette is able to induce micronuclei in oral mucosa cells, so the micronucleus test is a suitable method for predicting oral cancer risk.