Electronic cigarettes (e-cigarettes) have been acknowledged as having the potential to be substantially less harmful than smoked tobacco by an increasing number of public health authorities. Despite this, U.S. adults remain poorly informed about the relative harm of these products compared to continued combustible cigarette smoking. To quantify this, we analysed the data from the longitudinal and nationally representative Population Assessment of Tobacco and Health (PATH) study to assess the perceived relative harm of e-cigarettes amongst US adults between 2013 (wave 1) and 2019 (wave 5). Analysis showed that in wave 1 over half of participants (53%) believed e-cigarettes to be as harmful as or more harmful than combustible cigarettes which increased further over time (65% in wave 2, 72% in wave 3, 77% in wave 4 and 82% in wave 5). Among current adult U.S. smokers, 43% believed e-cigarettes to be as harmful as or more harmful than smoking in wave 1, which increased to 59% in wave 2, 69% in wave 3, 76% in wave 4, and 82% in wave 5. The longitudinal nature of the PATH study shows perceptions of the relative harm of e-cigarettes compared with cigarettes has worsened in the U.S. and are particularly strong in current adult smokers. It is therefore likely that adult smokers may not even try an e-cigarette as an alternative to smoking due to inaccurate beliefs about their relative harmfulness. Correcting these misperceptions with a clear, consistent, public health message may help more U.S. adult smokers, who would otherwise continue to smoke, to transition away from combustible cigarettes to potentially less harmful e-cigarette products, and to accelerate tobacco harm reduction strategies.