Although e-cigarette use is on the rise, there is little understanding of cognitive-based individual difference factors that maintain maladaptive e-cigarette beliefs and dependence. The present investigation sought to test a theoretically-driven interactive model of e-cigarette health literacy and anxiety sensitivity (AS; fear of the consequences of anxiety) among 537 e-cigarette users (50.7% female, Mage = 35.2 years, SD = 10.1) in terms of perceived benefits and risks of e-cigarette use as well as dependence. Results indicated a significant interaction between e-cigarette health literacy and AS. The significant interaction effect for each dependent variable was evident over and above the main effects as well as the covariates of sex, income, education, and dual cigarette use (e-cigarette dependence was also controlled for the models of perceived benefits and risks). The form of this interaction indicated that greater e-cigarette health literacy was more strongly related to greater perceived benefits and risks of e-cigarette use as well as dependence among those with higher, relative to lower, AS. Overall, the current data suggest that individual differences in e-cigarette health literacy and AS may represent two important factors to consider in e-cigarette beliefs and dependence. This study provides the first empirical evidence of the potential role of two cognitive factors in relation to e-cigarette use beliefs and behavior. These data suggest future clinical research may benefit by understanding the potential therapeutic role of e-cigarette health literacy and AS for e-cigarette use behavior.