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Americans have a shorter life expectancy compared with residents of almost all other high-income countries. We aim to estimate the impact of lifestyle factors on premature mortality and life expectancy in the US population.Using data from the Nurses’ Health Study (1980–2014; n=78 865) and the Health Professionals Follow-up Study (1986–2014, n=44 354), we defined 5 low-risk lifestyle factors as never smoking, body mass index of 18.5 to 24.9 kg/m2, ≥30 min/d of moderate to vigorous physical activity, moderate alcohol intake, and a high diet quality score (upper 40%), and estimated hazard ratios for the association of total lifestyle score (0–5 scale) with mortality. We used data from the NHANES (National Health and Nutrition Examination Surveys; 2013–2014) to estimate the distribution of the lifestyle score and the US Centers for Disease Control and Prevention WONDER database to derive the age-specific death rates of Americans. We applied the life table method to estimate life expectancy by levels of the lifestyle score.During up to 34 years of follow-up, we documented 42 167 deaths. The multivariable-adjusted hazard ratios for mortality in adults with 5 compared with zero low-risk factors were 0.26 (95% confidence interval [CI], 0.22–0.31) for all-cause mortality, 0.35 (95% CI, 0.27–0.45) for cancer mortality, and 0.18 (95% CI, 0.12–0.26) for cardiovascular disease mortality. The population-attributable risk of nonadherence to 5 low-risk factors was 60.7% (95% CI, 53.6–66.7) for all-cause mortality, 51.7% (95% CI, 37.1–62.9) for cancer mortality, and 71.7% (95% CI, 58.1–81.0) for cardiovascular disease mortality. We estimated that the life expectancy at age 50 years was 29.0 years (95% CI, 28.3–29.8) for women and 25.5 years (95% CI, 24.7–26.2) for men who adopted zero low-risk lifestyle factors. In contrast, for those who adopted all 5 low-risk factors, we projected a life expectancy at age 50 years of 43.1 years (95% CI, 41.3–44.9) for women and 37.6 years (95% CI, 35.8–39.4) for men. The projected life expectancy at age 50 years was on average 14.0 years (95% CI, 11.8–16.2) longer among female Americans with 5 low-risk factors compared with those with zero low-risk factors; for men, the difference was 12.2 years (95% CI, 10.1–14.2).Adopting a healthy lifestyle could substantially reduce premature mortality and prolong life expectancy in US adults.