It is widely believed that e-cigarettes are less harmful than conventional cigarettes because they have a lower nicotine content. In contrast to this notion, several in vitro studies have evaluated and demonstrated the genotoxicity associated with e-cigarette smoking. However, there is a lack of human studies on the genotoxicity of e-cigarettes. This pilot study evaluated and compared indicators of genotoxicity in e-cigarette users, cigarette smokers, and nonsmokers. A total of 84 healthy participants, including 20 e-cigarette users, 31 cigarette smokers, and 33 nonsmokers, were recruited. Genotoxicity was evaluated by measuring tail moment (TM), tail length (TL), and % tail DNA intensity (%T) using the comet assay as an indicator of DNA damage in blood and detecting micronuclei in buccal cells with the buccal micronucleus (MN) cytome assay. Bivariate analyses showed that there was no significant difference in TM and TL between e-cigarette users and cigarette smokers, but in both groups, the three parameters were significantly higher than that in nonsmokers (p < 0.02). In contrast, the frequency of micronuclei in e-cigarette users (40%) was higher than that in cigarette smokers (27.5%). Our findings indicate that e-cigarettes have a similar genotoxic effect to regular cigarettes and, therefore, contradict the notion that e-cigarettes are safer than regular cigarettes.