ABSTRACT: Importance:The prevalence of the use of electronic cigarettes (e-cigarettes) in the United States has grown rapidly since their introduction to the market more than a decade ago. While several studies have demonstrated an association between combustible cigarette smoking and depression, the association between e-cigarette use and depression has not been thoroughly studied. Objective:To examine the association between e-cigarette use and depression in a nationally representative sample of the adult population in the United States. Design, Setting, and Participants:Cross-sectional study of the Behavioral Risk Factor Surveillance System database, 2016 to 2017. The Behavioral Risk Factor Surveillance System is the largest national telephone-based survey of randomly sampled adults in the United States. A total of 892?394 participants with information on e-cigarette use and depression were included. Data analysis was conducted in May 2019. Exposures:Electronic cigarette use status defined by self-report as never, former, or current use. Main Outcomes and Measures:Self-reported history of a clinical diagnosis of depression. Results:Of the 892?394 participants (414?326 [29.0%] aged ?60 years; 502?448 [51.3%] women), there were 28?736 (4.4%) current e-cigarette users, of whom 13?071 (62.1%) were aged between 18 and 39 years. Compared with never e-cigarette users, current e-cigarette users were more likely to be single, male, younger than 40 years, and current combustible cigarette smokers (single, 120?797 [24.3%] vs 10?517 [48.4%]; men, 318?970 [46.6%] vs 14?962 [60.1%]; aged 18-39 years, 129?085 [32.2%] vs 13?071 [62.1%]; current combustible cigarette use, 217?895 [7.9%] vs 8823 [51.8%]). In multivariable adjusted models, former e-cigarette users had 1.60-fold (95% CI, 1.54-1.67) higher odds of reporting a history of clinical diagnosis of depression than never users, whereas current e-cigarette users had 2.10 (95% CI, 1.98-2.23) times higher odds. Additionally, higher odds of reporting depression were observed with increased frequency of use among current e-cigarette users compared with never users (daily use: odds ratio, 2.39; 95% CI, 2.19-2.61; occasional use: odds ratio, 1.96; 95% CI, 1.82-2.10). Similar results were seen in subgroup analyses by sex, race/ethnicity, smoking status, and student status. Conclusions and Relevance:This study found a significant cross-sectional association between e-cigarette use and depression, which highlights the need for prospective studies analyzing the longitudinal risk of depression with e-cigarette use. If confirmed by other study designs, the potential mental health consequences may have regulatory implications for novel tobacco products.