Background: Medical research has proved that cigarette smoking endangered body health and also delayed recovery from injuries and diseases. This study was conducted to examine the histopathological changes induced by smoking and to evaluate the expression of p53 and cytokeratin 5 in the gingiva of smokers and heavy smokers.Methods: Gingival biopsies were obtained from systemically and periodontally healthy 45 individuals, of middle age during extraction of badly decayed teeth. Five were non smokers and represented the control group, 20 were light smokers and 20 others were heavy smokers. The specimens were subjected to histological and immunohistochemical study as well as morphometric and statistical evaluation of p53 and cytokeratin 5 expression.Results: Hyperplastic and mild to moderate dysplastic changes were reported in the gingiva of light smokers. Whereas the heavy smokers experienced more severe pathological changes, so that carcinoma in situ and early invasive squamous cell carcinoma was detected. The immunohistochemical results revealed a highly significant increase in the area percentage level of cytokeratin5 and p53 in the gingival of light and heavy smokers compared to the control group. The same correlation existed between heavy and light smokers with p≤0.001.In term of optical density; there was a highly significant increase in both biomarkers in light smokers compared to the control. However, p53 represented only a significant increase in heavy smokers compared to light smokers (p<0.05).On the other hand no significant correlation was reported for the intensity of cytokeratin5 between heavy and light smoker groups (p>0.05).Conclusions: Smoking induced hyperplastic and dysplastic changes in gingiva of smokers that were severer in heavy smokers to the extent of premalignant and malignant tissue alterations.