Electronic nicotine delivery system (ENDS) products have the potential to provide nicotine to adult tobacco consumers while reducing exposure to combustion-related toxicants. This study evaluated changes in biomarker(s) of exposure (BoE) to combustion-related toxicants after smokers switched from their usual brand (UB) non-menthol cigarettes to one of three Vuse Original ENDS products (Vuse Vibe, Vuse Ciro, and Vuse Solo) or to abstinence. The BoE evaluated represent constituents for which validated biomarkers exist and that were recommended for evaluation in e-liquids and aerosols by the FDA in the 2016 (Draft) and 2019 (Final) ENDS Premarket Tobacco Product Application guidance documents, and/or constituents identified by FDA as harmful and potentially harmful constituents (HPHCs) in tobacco products or tobacco smoke. Subjects smoked their UB cigarette ad libitum for two days, then were randomized to one of three Vuse ENDS products for a 5-day ad libitum use or abstinence. Twelve urinary (including nicotine and five metabolites) and one blood BoE were measured at both baseline and day 5. Changes in BoE from baseline to day 5 were determined and the percent change of mean was calculated for each cohort. Results showed an overall decrease in BoE across the three product-switch and abstinence cohorts. Blood carboxyhemoglobin decreased 51-55 % in all four study cohorts. Urinary biomarkers decreased between 40 - 95 % for aromatic amines, mercapturic acids, tobacco-specific nitrosamines, and 3-hydroxy-benzo[a]pyrene in all four study cohorts. However, smaller changes (5 - 30 % decrease) in total nicotine equivalents were observed from baseline to day 5 for each of the three product-switch cohorts versus a > 95 % decrease in the abstinence cohort. Nicotine levels within the product-switch cohorts increased steadily throughout the study. In this study, smokers who were switched to the ENDS products had reductions in combustion-related BoE similar to the reductions observed in the abstinence cohort.