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 submitted to dental X-ray using two anatomic sites: buccal mucosa and lateral border of the tongue. A total of 15 heavy smokers and 17 non-smokers were submitted to panoramic dental radiography for orthodontic reasons. Individuals had epithelial cells from cheek and lateral border of the tongue mechanically exfoliated, placed in fixative, and dropped in clean slides which were checked for the above nuclear phenotypes. The results pointed out no significant statistically differences (p > 0.05) of micronucleated oral mucosa cells before versus after X-ray exposure for both oral sites evaluated either to smokers or to non-smokers. X-ray exposure was able to increase other nuclear alterations closely related to cytotoxicity such as karrhyorexis, pyknosis, and karyolysis for two groups evaluated. Nevertheless, the most pronunciated effects were found to lateral border of the tongue of smokers. In summary, these data indicate that panoramic X-ray is able to induce cellular death in oral mucosa cells. It seems that lateral border of the tongue is more sensitive site to cytotoxic insult induced by ionizing radiation combined with continuous cigarette smoke exposure.