E-cigarette use has been increasing in recent years, and its ultimate public health impact is still unknown. In order to assess the addictive liability of these products, research is needed to investigate the roles of nicotine and other factors on psychological and physical effects of “vaping.” The goal of the current study was to investigate the role of expectancies, nicotine delivery, and their interactions on the effects of e-cigarette use via a balanced-placebo experiment. In this design, drug dosage (contains nicotine or not) was crossed with instructions (told nicotine or non-nicotine) during ad-lib e-cigarette use sessions by 128 current e-cigarette users. This design allows for parsing of the causal role of expectancies and pharmacology, as well as their interaction. Dependent variables included both psychological outcomes (cravings for cigarettes and e-cigarettes, mood, satisfaction, reward) and physiological variables (hunger, attention, aversion, respiratory tract sensations). Among cigarette smokers (n=52), a significant main effect of instruction emerged on reductions in craving to smoke, although moderation analyses revealed that this effect was limited to males. Overall, significant drug X instruction interactions were found on craving to vape, psychological reward, and enjoyment of respiratory tract sensations, indicating synergistic causal influences of both expectancies and nicotine. Expectancies, smoking status, and gender moderated some of these effects. The results of this study identified effects of e-cigarettes that were driven by either nicotine, cognitive drug expectancies, or both. Results should be considered in the context of methodological and theoretical limitations. This study contributes to the understanding of motivational influences that may affect the initiation and maintenance of e-cigarette use, which may guide the development of public health and clinical interventions.