Background Recent estimates indicated substantially replacing cigarettes by e-cigarettes would, during 2016–2100, reduce US deaths and life-years lost (millions) by 6.6 and 86.7 (Optimistic Scenario) and 1.6 and 20.8 (Pessimistic). To provide additional insight we use alternative modelling based on a shorter period (1991–2040), four main smoking-associated diseases, deaths aged 30–79 years, and a full product history. We consider variations in: assumed effective dose of e-cigarettes versus cigarettes (F); their relative quitting rate (Q); proportions smoking after 10 years (X); and initiation rate (I) of vaping, relative to smoking. Methods We set F = 0.05, X = 5%, Q = 1.0 and I = 1.0 (Main Scenario) and F = 0.4, X = 10%, Q = 0.5 and I = 1.5 (Pessimistic Scenario). Sensitivity Analyses varied Main Scenario parameters singly; F from 0 to 0.4, X 0.01% to 15%, and Q and I 0.5 to 1.5. To allow comparison with prior work, individuals cannot be dual users, re-initiate, or switch except from cigarettes to e-cigarettes. Results Main Scenario reductions were 2.52 and 26.23 million deaths and life-years lost; Pessimistic Scenario reductions were 0.76 and 8.31 million. These were less than previously, due to the more limited age-range and follow-up, and restriction to four diseases. Reductions in deaths (millions) varied most for X, from 3.22 (X = 0.01%) to 1.31 (X = 15%), and F, 2.74 (F = 0) to 1.35 (F = 0.4). Varying Q or I had little effect. Conclusions Substantial reductions in deaths and life-years lost were observed even under pessimistic assumptions. Estimates varied most for X and F. These findings supplement literature indicating e-cigarettes can importantly impact health challenges from smoking.