To examine whether lower extremity strength (LES) is predictive of all-cause mortality, independent of physical activity and among those with vary levels of sedentary behavior. Data from the 1999-2002 National Health and Nutrition Examination Survey was used (N = 2768; 50-85 years). Peak isokinetic knee extensor strength was objectively measured, sedentary behavior and physical activity were self-reported, and mortality was assessed via the National Death Index, with follow-up through 2011. Participants were followed for up to 12.6 years with the weighted average follow-up period lasting 9.9 years (standard error, 1.13). In the sample, 321,996 person-months occurred with a mortality rate of 2.1 deaths per 1000 person-months. After adjustments (including physical activity), for every 15 N increase in LES, participants had a 7 % reduced risk of all-cause mortality (HR = 0.93; 95 % CI 0.91-0.95; P < 0.001). When adding a three-level sedentary behavior variable (< 2, 2-4, 5+ h/day) as a covariate in this model, results were unchanged (HR = 0.93; 95 % CI 0.92-0.96; P < 0.001). Similarly, when sedentary behavior was included as a continuous covariate in the model, results regarding the relationship between LES and mortality were unchanged (HR = 0.94; 95 % CI 0.91-0.96; P < 0.001). There was no evidence of statistical interaction between LES and sedentary behavior on all-cause mortality (HRinteraction = 1.01; 95 % CI 0.92-1.10; P = 0.88). LES was inversely associated with all-cause mortality, and this association was unchanged when considering the participant's sedentary behavior.