Electronic nicotine delivery systems (ENDS) are a potentially lower-risk tobacco product which could help smokers switch completely away from cigarettes. However, the lack of strong evidence to date of a measurable, population-level effect on reducing smoking has generated skepticism about ENDS’ potential benefits. This study examines whether increased US ENDS sales have been associated with reduced cigarette sales. Retail data on weekly per-capita cigarette and ENDS purchases in the USA during 2014–2019 were obtained from a national sample of brick-and-mortar retail outlets. Trends in cigarette sales were modeled before (2014–2016) ENDS had a substantial market share, and, after adjusting for macroeconomic factors, projected into the post-period (2017–2019). Actual cigarette sales were lower than projected sales (by up to 16% across the post-period), indicating a substantial “cigarette shortfall” in the post-period. To explore whether general (i.e., inclusive of potentially many mechanisms) substitution by ENDS can explain the cigarette shortfall, its association with per-capita ENDS volume sales was examined. Higher ENDS sales were significantly associated with a greater cigarette shortfall: for every additional per-capita ENDS unit, cigarette sales were 1.4 packs-per-capita lower than expected (B = 1.4, p < .0001). Error correction models which account for spurious correlation yielded similar results. These findings support ENDS serving as a substitute for cigarettes (through potentially many mechanisms including cigarette price), causing cigarette consumption to decline. Since ENDS potentially pose lower risk than cigarettes, this general substitution effect suggests that risk-proportionate tobacco regulation could mitigate the tobacco-related health burden.