Smoking negatively affects the prognosis of periodontal disease by impairing tissue healing. While micronucleus is the most popular parameter for demonstrating DNA damage, inflammatory cell and vascular densities are the most evaluated parameters for determining histopathologic changes in the periodontium. This study aimed to study the effects of periodontitis and cigarette smoking on genotoxic changes in exfoliated oral epithelial cells and histopathologic changes in periodontal tissue. A crosssectional study was conducted between November 2018 and July 2019 at a dental university hospital in Turkey, and registered as NCT05484765. Eighty systemically healthy subjects were divided into four groups according to periodontal status and smoking habits: 20 smokers with generalized periodontitis (SGP), 20 nonsmokers with generalized periodontitis (NGP), 20 smokers with healthy periodontium (SHP), and 20 nonsmokers with healthy periodontium (NHP). For each study participant, full-mouth clinical periodontal parameters (CPPs) were measured, smear samples were taken from buccal and gingival mucosa, and periodontal tissue was biopsied from the maxillary molars. Cytogenetic and histopathologic assays (primary and secondary outcomes) were conducted using Feulgen reaction and hematoxylin-eosin staining, respectively. The mean CPPs of healthy periodontium groups were lower than generalized periodontitis groups. No significant differences were found between other groups regarding CPPs. Buccal micronuclei counts in groups decreased with the highest to lowest counts occurring in the order SGP > SHP > NGP > NHP. Gingival micronuclei counts in groups decreased from SGP > SHP > NGP = NHP. The most intense inflammatory cell and vascular densities occurred in SGP and NGP groups, respectively; and the mildest values were in healthy periodontium groups. Histopathological damage score decreased significantly by group in order SGP > NGP > SHP > NHP. The synergy arising from the combination of smoking and periodontitis exposures exacerbates genotoxic and histopathologic damage in oral cells and the periodontium.Abbreviations: BOP = bleeding on probing, CPPs = full-mouth clinical periodontal parameters, NGP = nonsmokers with generalized periodontitis, NHP = nonsmokers with clinically healthy periodontium, PD = probing depth, SGP = smokers with generalized periodontitis, SHP = smokers with clinically healthy periodontium.