Background/Aim: Cytogenetic biomarkers such as micronuclei (MN) are used for the evaluation of exposure to carcinogens and genotoxic effects in oral epithelial cells. Tobacco is one of the strongest carcinogens responsible for the development of cancer in oral mucosa. The aim of this study was to compare the genotoxic effect of waterpipe smoking with that of cigarette smoking. Methods: This case-control study was performed on 30 waterpipe smokers, 30 cigarette smokers, and 30 nonsmokers. Buccal exfoliated cells were prepared using cytobrushes and stained with the Papanicolaou technique. The cytologic slides were examined under a light microscope for counting the number of MN and the number of cells with MN per 1,000 epithelial cells. Results: The mean number ± standard deviation (SD) of MN in waterpipe smokers, cigarette smokers, and nonsmokers was 7.55 ± 5.530, 4.95 ± 5.633, and 2.00 ± 2.406, respectively. The mean number ± SD of cells with MN in waterpipe smokers, cigarette smokers, and nonsmokers was 6.20 ± 4.830, 3.50 ± 3.832, and 1.45 ± 1.701, respectively. Numbers of cells with MN differed significantly between waterpipe smokers and cigarette smokers (p = 0.04) and between waterpipe smokers and nonsmokers (p < 0.001). Numbers of MN differed significantly between waterpipe smokers and nonsmokers (p < 0.001). Numbers of MN did not differ significantly between waterpipe smokers and cigarette smokers (p = 0.10). Numbers of MN and of cells with MN did not differ significantly between cigarette smokers and nonsmokers (p = 0.06 and p = 0.052, respectively). Conclusions: Waterpipe smoking is associated with a significantly higher frequency of MN, and it seems that waterpipe smoking has a greater genotoxic effect than cigarette smoking.