The authors examined the joint associations of adiposity (assessed by body mass index (BMI; weight (kg)/height (m)(2)) and waist circumference) and physical activity with mortality to evaluate whether physical activity protects against the adverse effects of high adiposity. Using data on 185,412 men and women aged 51-72 years participating in the National Institutes of Health-AARP Diet and Health Study, the authors assessed all-cause mortality over 10 years (1996-2006). Overweight (BMI 25-<30), obesity (BMI > or =30), a large waist circumference (men: > or =102 cm; women: > or =88 cm), and low physical activity were each independent predictors of mortality. Compared with normal-weight persons (BMI 18.5-<25) who were physically active (>7 hours/week of moderate physical activity), mortality risks were 1.62 (95% confidence interval (CI): 1.50, 1.75) for inactive normal-weight persons, 1.79 (95% CI: 1.37, 2.33) for active morbidly obese (BMI > or =35) persons, and 3.45 (95% CI: 2.79, 4.00) for inactive morbidly obese persons. Similar results were found for the combined relation of BMI and vigorous physical activity. Inactive persons with a large waist circumference had 2 times' greater mortality risk than active persons with a normal waist circumference. High physical activity attenuated but did not eliminate the increased mortality risk associated with obesity. Preventing weight gain and promoting physical activity in older persons may lower mortality risk.