BACKGROUND: Whether higher levels of physical activity can counteract the elevated risk of death associated with adiposity is controversial. METHODS: We examined the associations of the body-mass index and physical activity with death among 116,564 women who, in 1976, were 30 to 55 years of age and free of known cardiovascular disease and cancer. RESULTS: During 24 years of follow-up, 10,282 deaths occurred - 2370 from cardiovascular disease, 5223 from cancer, and 2689 from other causes. Mortality rates increased monotonically with higher body-mass-index values among women who had never smoked (P for trend <0.001). In combined analyses of all participants, adiposity predicted a higher risk of death regardless of the level of physical activity. Higher levels of physical activity appeared to be beneficial at all levels of adiposity but did not eliminate the higher risk of death associated with obesity. As compared with women who were lean (i.e., they had a body-mass index lower than 25) and active (they spent 3.5 or more hours exercising per week), the multivariate relative risks of death were 1.55 (95 percent confidence interval, 1.42 to 1.70) for lean and inactive women, 1.91 (95 percent confidence interval, 1.60 to 2.30) for women who were obese (defined as a body-mass index of 30 or higher) but active, and 2.42 (95 percent confidence interval, 2.14 to 2.73) for inactive, obese women. Even modest weight gain during adulthood, independent of physical activity, was associated with a higher risk of death. We estimate that excess weight (defined as a body-mass index of 25 or higher) and physical inactivity (less than 3.5 hours of exercise per week) together could account for 31 percent of all premature deaths, 59 percent of deaths from cardiovascular disease, and 21 percent of deaths from cancer among nonsmoking women. CONCLUSIONS: Both increased adiposity and reduced physical activity are strong and independent predictors of death.