Abstract Introduction E-cigarettes (ECs) may benefit smokers with mental health conditions who are more likely to smoke, and smoke more heavily, than those without mental health conditions. This could be undermined if harm misperceptions in this group are high as is the case in the general population. This study aimed to assess EC harm perceptions relative to cigarettes as a function of mental health status and a variety of characteristics. Methods Data were collected from 6531 current smokers in 2016/2017 in household surveys of representative samples of adults. The associations of mental health status (self-reported mental health condition and past year treatment), smoking and EC use characteristics, and characteristics relating to use of potential information sources with harm perceptions of ECs relative to cigarettes (measured by correct response “less harmful” vs. wrong responses “more harmful,” “equally harmful,” “don’t know”) were analyzed with logistic regression. Results A similar proportion of smokers without mental health conditions (61.5%, 95% CI 60.1–62.9) and with mental health conditions (both with [61.3%, 95% confidence interval [CI] 58.7–63.8] and without past year treatment [61.5%, 95% CI 58.1–64.7]) held inaccurate EC harm perceptions (all P > 0.05). Being female, nonwhite, aged 25–34 compared with 16–24, from lower social grades (C2, D, and E), not having post-16 qualifications, no EC experience, a daily smoker, unmotivated to quit <1 month, non-internet user and non-broadsheet reader were all associated with more inaccurate harm perceptions (all p < .05). Conclusions The majority of smokers in England have inaccurate harm perceptions of ECs regardless of mental health status. Implications This study is the first to use a nationally representative sample in order to investigate whether smokers with and without mental health conditions differ with regard to harm perceptions of ECs. Findings show that the majority of smokers in England hold inaccurate harm perceptions of ECs, and this does not differ as a function of mental health status. A number of characteristics associated with disadvantaged groups were significantly associated with inaccurate harm perceptions. These findings highlight the need to improve awareness and understanding among disadvantaged groups regarding the relative harms of ECs compared with tobacco.