Comparisons of systemic exposure to toxicants during monitored cigarette smoking, electronic cigarette (e-cigarette) use and abstention are needed to enhance our understanding of the risks of e-cigarette use (vaping). In a crossover study, we measured 10 mercapturic acid metabolites of volatile organic compounds (VOCs) in 24-h urine samples collected from 36 dual users (8 women) of e-cigarettes and cigarettes during two days of ad libitum vaping or cigarette-only use, and two days of enforced abstention. Concentrations of VOC metabolites were higher during smoking compared to vaping, except for the methylating agents metabolite. The fold-difference in concentrations when smoking relative to vaping ranged from 1.31 (1.06-1.61) (GM, 95% CI) (1,3-butadiene) to 7.09 (5.88-8.54) (acrylonitrile). Metabolites of acrylamide [fold difference of 1.21 (1.03-1.43)] and benzene [1.46 (1.13-1.90)] were higher during vaping compared to abstention. The 1,3-butadiene and propylene oxide metabolites were higher in variable-power tank users compared to users of cig-a-likes. E-cigarettes expose users to lower levels of toxic VOCs compared to cigarette smoking, supporting their harm reduction potential among smokers. However, some e-cigarettes expose users to VOCs such as acrylamide, benzene, and propylene oxide, and may pose health risks to nonsmoking users. The results of our study will inform regulators in assessing e-cigarettes with respect to the balance between its potential harm reduction for adult smokers and risk to nonsmoking users.