Informing adults who smoke (AWS) that completely switching to electronic nicotine delivery systems (ENDS) reduces their exposure to harmful chemicals could prompt them to switch. However, it would be problematic if such reduced-exposure messages prompted ENDS use by adults not currently using tobacco (Former Users and Never Users of tobacco). This study assessed the effect of a reduced-exposure message for JUUL ENDS, presented in a video ad, on behavioral intentions among 3485 AWS, 1756 Dual Users (of cigarettes and ENDS), 1857 Former Users and 5459 Never Users. In a randomized experiment, participants viewed an ad for JUUL with or without a reduced-exposure message. Exposure to the reduced-exposure message significantly increased AWS’ Openness to Try ENDS, while significantly decreasing it among Nonusers, resulting in a significant message × user group interaction. Responses of young adults (18–24 years) did not differ from those of older adults (30+), and message exposure did not increase Young Adult Nonusers’ Openness to Try. The message’s effect on AWS’ Openness to Try was completely mediated by its effects on AWS’ perception of the risk of ENDS use compared to smoking cigarettes. The reduced-exposure message resulted in a pattern of behavioral intentions consistent with a favorable impact on population health.