Electronic cigarettes (e-cigarettes) are becoming increasingly popular. The popularity of fruit flavors among e-cigarette users suggests that sweet taste may contribute to e-cigarette appeal. We therefore tested whether sweet taste potentiates the reinforcing effects of nicotine. Using a conditioning paradigm adapted to study e-cigarettes, we tested whether exposure to flavored e-cigarettes containing nicotine plus sweet taste would be more reinforcing than unsweetened e-cigarettes. Sixteen light cigarette smokers smoked 4 distinctly colored e-cigarettes containing sweetened and unsweetened flavors with or without nicotine for 2 days each. Brain response was then assessed to the sight and smell of the 4 exposed e-cigarettes using fMRI. After exposure, sweet-paired flavors were wanted (p = .024) and tended to be liked (p = .053) more than nicotine-paired flavors. Moreover, sweet taste supra-additively increased liking for nicotine-paired flavors in individuals who did not show increased liking for nicotine alone (r = −.67, p = .005). Accordingly, cues predicting sweet compared to non-sweet flavors elicited a stronger response in the nucleus accumbens (NAcc, p SVC = .050) and the magnitude of response to the sight (p SVC = .022) and smell (p SVC = .017) of the e-cigarettes correlated with changes in liking. By contrast, the sight and smell of cues predicting nicotine alone failed to elicit NAcc response. However, the sight and smell of e-cigarettes paired with sweet+nicotine (p SVC = .035) produced supra-additive NAcc responses. Collectively, these findings demonstrate that sweet taste potentiates the reinforcing effects of nicotine in e-cigarettes resulting in heightened brain cue-reactivity.