Background Sedentary behavior is related to increased mortality risk. Whether such elevated risk can be offset by enhanced physical activity has not been examined using accelerometry data. Materials and Methods We examined the relations of sedentary time and physical activity to mortality from any cause using accelerometry data among 1,677 women and men aged 50 years or older from the National Health and Nutrition Examination Survey (NHANES) 2003-2004 cycle with follow-up through December 31, 2006. Results During an average follow-up of 34.67 months and 4,845.42 person-years, 112 deaths occurred. In multivariate Cox proportional hazard models, greater sedentary time (>= median of 8.60 hours/day) was associated with increased risk of mortality from any cause (relative risk (RR) = 2.03; 95% confidence interval (CI) = 1.09-3.81). Low level of moderate to vigorous physical activity (< median of 6.60 minutes/day) was also related to enhanced allcause mortality risk (RR = 3.30; 95% CI = 1.33-8.17). In combined analyses, greater time spent sedentary and low levels of moderate to vigorous physical activity predicted a substantially elevated all-cause mortality risk. As compared with the combination of a low sedentary level and a high level of moderate to vigorous physical activity, the risks of mortality from all causes were 4.38 (95% CI = 1.26-15.16) for low levels of both sedentary time and physical activity, 2.79 (95% CI = 0.77-10.12) for greater time spent sedentary and high physical activity level, and 7.79 (95% CI = 2.26-26.82) for greater time spent sedentary and low physical activity level. The interaction term between sedentary time and moderate to vigorous physical activity was not statistically significant (p = 0.508). Conclusions Both high levels of sedentary time and low levels of moderate to vigorous physical activity are strong and independent predictors of early death from any cause. Whether a high physical activity level removes the increased risk of all-cause mortality related to sedentariness requires further investigation.