Key Points Question Are electronic cigarette (e-cigarette) users exposed to known tobacco-related toxicants and, if so, how does the exposure compare with that of combusted tobacco cigarettes? Findings In this population-based cohort study of 5105 participants, current exclusive e-cigarette users had greater concentrations of biomarkers of nicotine, tobacco-specific nitrosamines, volatile organic compounds, and metals compared with never tobacco users. However, these concentrations were lower than those observed in current exclusive cigarette smokers and dual users of both products. Meaning Use of e-cigarettes appears to be associated with exposure to known tobacco-related toxicants, but the exposure is reduced compared with cigarette smoking.