The authors sought to examine how much sedentary time needs to be replaced by light or moderate–vigorous physical activity in order to reduce frailty and protect against mortality. The authors built isotemporal substitution models to assess the theoretical effect of replacing sedentary behavior with an equal amount of light or moderate–vigorous activity on frailty and mortality in community-based adults aged 50 years and older. Controlling for age, sex, body mass index, marital status, race, education, employment status, and National Health and Nutrition Examination Study cycle, replacing 1 hr of sedentary time with moderate–vigorous or light physical activity daily was associated with a lower frailty index. For mortality, results varied based on frailty level. Replacing sedentary behavior with moderate–vigorous exercise was associated with lower mortality risk in vulnerable individuals; however, replacing sedentary behavior with light activity was associated with lower mortality risk in frailer individuals.