Previous studies suggest that a substantial number of deaths could be prevented annually by increasing population levels of physical activity. However, previous estimates have relied on convenience samples, used self-reported physical activity data, and assumed relatively large increases in activity levels (eg, more than 30 minutes per day). The potential public health benefit of changing daily physical activity by a manageable amount is not yet known. In this study, we used accelerometer measurements (1) to examine the association of physical activity and mortality in a population-based sample of US adults and (2) to estimate the number of deaths prevented annually with modest increases in moderate-to-vigorous physical activity intensity (MVPA).