Introduction: The US FDA seeks to ensure that new tobacco products are appropriate for the protectionof the public health and recommends assessment of tobacco-related morbidity as well as mortality. A simulation model that predicts the effect of e-cigarettes on tobacco use and mortality was extended to approximate effects on morbidity, as measured by US health care costs. Methods: The US adult population was simulated through year 2100, using randomly generated tobacco product use histories including initiation, cessation, and switching between products. Smokers and e-cigarette users also transitioned to and from dual use, which affected average cigarettes smoked per day and cigarette quit rates. The model predicted premature deaths avoided by e-cigarettes. Although e-cigarettes may benefit smokers who switch completely to them, benefits are less certain for other groups. The net effect depends on uncertain transition rates and the Excess Relative Risk (ERR) experienced by e-cigarette users relative to cigarette smokers. Sensitivity to each input was tested systematically, and a hypothetical “break-even” ERR, which would reduce a product’s net population benefit to zero in terms of avoided premature deaths, was calculated. Tobacco-attributable morbidity costs were assumed proportional to tobacco-attributable mortality and were scaled from recent US estimates. Results: Simulations suggested that e-cigarettes would avoid 2.5 million premature deaths and an average of $15.6 billion/year health care costs in the US population through 2100 in a base scenario, and provide a net benefit in all except extreme scenarios. The base-case break-even ERR was over 50% relative to cigarettes. Conclusions: These simulations show that e-cigarettes would very likely benefit the overall health and health care costs of US adults, despite uncertainties in ERR and other inputs.