Objective We evaluated the specific association between a Fitness Fat Index (FFI) and Alzheimer's-specific mortality among a national sample of the broader U.S. adult population. Methods FFI was calculated as cardiorespiratory fitness (CRF) divided by waist-to-height ratio (WHR). Data from the 1999–2006 National Health and Nutrition Examination Survey (NHANES) were used to identify 16,146 participants, ages 20–85. Data from participants in these cycles were linked to death certificate data from the National Death Index. Person-months of follow-up were calculated from the date of the interview until date of death or censoring on December 31, 2011, whichever came first. Results In a Cox proportional hazard model, for every 1 FFI unit increase, participants had a 14% reduced hazard of Alzheimer-specific death (HR = 0.86; 95% CI: 0.83–0.90; P < 0.001). When including diabetes and hypertension (via physician-diagnosis) as covariates, results were unchanged (HR = 0.87; 95% CI: 0.82–0.91; P < 0.001). Results were also unchanged when restricting the sample to those 50+ years (HR = 0.92; 95% CI: 0.88–0.97; P = 0.005) or stratifying by men (HR = 0.85; 95% CI: 0.81–0.91; P < 0.001) or women (HR = 0.86; 95% CI: 0.79–0.94; P = 0.002). Conclusion In this national sample of individuals at risk for Alzheimer's disease, increased FFI was associated with reduced risk of Alzheimer's-specific death. Thus, a more favorable fitness-to-fatness ratio is associated with reduced risk of Alzheimer's-specific mortality, underscoring the importance of fitness promoting and fatness reducing strategies.