Background: Whether national physical activity recommendations are related to mortality benefit is incompletely understood. Methods: We prospectively examined physical activity guidelines in relation to mortality among 252 925 women and men aged 50 to 71 years in the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study. Physical activity was assessed using 2 self-administered baseline questionnaires. Results: During 1 265 347 person-years of follow-up, 7900 participants died. Compared with being inactive, achievement of activity levels that approximate the recommendations for moderate activity (at least 30 minutes on most days of the week) or vigorous exercise (at least 20 minutes 3 times per week) was associated with a 27% (relative risk [RR], 0.73; 95% confidence interval [CI], 0.68-0.78) and 32% (RR, 0.68; 95% CI, 0.64-0.73) decreased mortality risk, respectively. Physical activity reflective of meeting both recommendations was related to substantially decreased mortality risk overall (RR, 0.50; 95% CI, 0.46-0.54) and in subgroups, including smokers (RR, 0.48; 95% CI, 0.44-0.53) and nonsmokers (RR, 0.54; 95% CI, 0.45-0.64), normal weight (RR, 0.45; 95% CI, 0.39-0.52) and overweight or obese individuals (RR, 0.48; 95% CI, 0.44-0.54), and those with 2 h/d (RR, 0.53; 95% CI, 0.44-0.63) and more than 2 h/d of television or video watching (RR, 0.50; 95% CI, 0.45-0.55). Engaging in physical activity at less than recommended levels was also related to reduced mortality risk (RR, 0.81; 95% CI, 0.76-0.86). Conclusions: Following physical activity guidelines is associated with lower risk of death. Mortality benefit may also be achieved by engaging in less than recommended activity levels.