The main goal of the present study was to determine whether the perceived relative harm of e-cigarettes versus combustible cigarettes changed between 2012 and 2015. Over this period, there was an increase in perceiving e-cigarettes to be equally or more harmful than cigarettes. Similarly, the belief that e-cigarettes are addictive increased among U.S. adults in 2012–2015. Adults who perceived e-cigarettes to be addictive, had never used e-cigarettes, were female, or aged 25–34 years were more likely to misperceive the harm of e-cigarettes—to believe that e-cigarettes are equally or more harmful than combustible cigarettes.