ABSTRACT: Importance:Relapse to smoking among former smokers is a serious clinical concern, and use of electronic nicotine delivery systems (ENDS) has been proposed as a new risk factor for relapse. Understanding the specificity of this risk can help guide clinical practice and lead to improved health outcomes. Objective:To assess the associations of ENDS use with cigarette smoking relapse among adult former cigarette smokers. Design, Setting, and Participants:This cohort study examined data from the Population Assessment of Tobacco and Health Study, waves 1 to 4 (2013-2018). Cox proportional hazards models were developed. This is an ongoing, nationally representative, longitudinal cohort study in the US. Participants included adult (≥18 years) former cigarette smokers who reported no tobacco product use at wave 1 (unweighted n = 2273), separated into recent former cigarette smokers (last smoked ≤12 months previously) and long-term former smokers (last smoked >12 months previously). Data analysis was conducted from July to August 2019. Exposures:Self-reported use of cigarettes, ENDS, and other tobacco products (ie, cigars, pipe tobacco, hookah, snus tobacco, other smokeless tobacco, and dissolvable tobacco) was assessed. Main Outcomes and Measures:Self-reported current (every day or some days) use of cigarettes at follow-up interviews. Results:Of 2273 adult former cigarette smokers, 51.8% (95% CI, 49.7%-53.8%) were women, 65.0% (95% CI, 62.6%-67.4%) were older than 50 years, and 79.5% (95% CI, 77.8%-81.2%) were non-Hispanic white participants. Use of ENDS was associated with significant risk of cigarette smoking relapse among recent former smokers (adjusted hazard ratio [AHR], 1.63; 95% CI, 1.04-2.53; unweighted n = 304) and among long-term former smokers (AHR, 3.79; 95% CI, 1.75-8.20; unweighted n = 1554). Use of other tobacco products was also associated with significant risk for cigarette smoking relapse among recent former smokers (AHR, 1.97; 95% CI, 1.27-3.05) and among long-term former smokers (AHR, 3.82; 95% CI, 1.91-7.66). Conclusions and Relevance:In this study, use of ENDS and other tobacco products was associated with increased risk of cigarette smoking relapse among former cigarette smokers who did not use any tobacco product at wave 1 of the PATH Study. For clinicians treating former smokers who have successfully quit all nicotine products, the implications are that use of ENDS products should be discouraged, just as use of all other tobacco products is discouraged.