Informing adults who smoke (AWS) that completely switching to e-cigarettes reduces their exposures to harmful chemicals could prompt them to switch to e-cigarettes. But it would be problematic if such messages prompted e-cigarette use by adults not using tobacco (Nonusers). This study assessed the effect of a reduced-exposure message on behavioral intentions among both these groups. In a randomized experiment, 3,485 AWS, 7,316 Nonusers (former- and never-users), and 1,756 adults using both cigarettes and e-cigarettes viewed an ad for JUUL e-cigarettes with or without a reduced-exposure message. Participants’ Openness-to-Try (OTT) and Openness-to-Use (OTU) JUUL were assessed. Exposure to the message significantly increased AWS’ OTT JUUL, while significantly decreasing it among Nonusers, resulting in a significant message x population interaction. The interaction was also significant for OTU; the message significantly increased OTU in AWS, and non-significantly decreased it among Nonusers. The message’s effect on AWS’ OTU was completely mediated by its effects on the perceived risk differential between JUUL use and smoking. Message exposure did not affect AWS’ intention to quit smoking, and decreased susceptibility to smoking among Nonusers Open to Using JUUL. The reduced-exposure message resulted in a pattern of behavioral intentions consistent with a favorable impact on population health.