Objectives: Given that nicotine is one of the most addictive substances and that adolescents who are exposed to nicotine via e-cigarettes can progress to conventional cigarette smoking, there is a need to identify youth who are susceptible to e-cigarette use and prevent them from initiating e- cigarette use. Susceptibility to e-cigarette use, defined as the absence of a firm decision not to use e-cigarettes, is a useful concept that can be used to predict e-cigarette initiation and identify youth who have high risk of initiating e-cigarettes. This study was conducted to investigate factors that affect youth susceptibility to e-cigarette use. Methods: Youth who have never smoked conventional cigarettes and who had seen or heard of e-cigarettes but never used them (N = 9,853) were drawn from the Population Assessment of Tobacco and Health (PATH) Study Wave 1 youth dataset collected from 2013–2014. Data were analyzed using logistic regression to investigate intrapersonal and environmental determinants of youth susceptibility to e-cigarette use. Results: Overall, 24.2% (n=2,410) of youth who have never used e-cigarettes were susceptible to e-cigarette use. Psychological problems and rebelliousness were associated with increased susceptibility. Ever use of alcohol, marijuana, and other substances and household secondhand smoke exposure were found to be risk factors. Perceptions of e-cigarettes as addictive and harmful worked as protective factors. Conclusions: The results revealed determinants of e-cigarette use susceptibility. Multi-level intervention approach is needed to prevent youth from being susceptible to e-cigarette initiation.