ABSTRACT Introduction/Purpose Fatigue is an established prognostic indicator of mortality risk. It remains unknown whether fatigability anchored to a physical task is a more sensitive prognostic indicator and whether sensitivity differs by prevalent chronic conditions. Methods 1,076 physically well-functioning participants aged ≥50 years in the Baltimore Longitudinal Study of Aging self-reported fatigue (unusual tiredness or low energy) and had perceived fatigability assessed after a standardized treadmill walk. All-cause mortality was ascertained by proxy contact and National Death Index linkage. Cox proportional hazards models estimated associations of perceived fatigability and fatigue with all-cause mortality, adjusting for demographic and clinical covariates. Interactions by chronic conditions were also examined. Results Each one-standard deviation higher in perceived fatigability, unusual tiredness, or low energy was associated with a higher relative hazard of all-cause mortality after covariate adjustment (fatigability: HR = 1.18, 95% CI: 1.03-1.36; unusual tiredness: HR = 1.25, 95% CI: 1.08-1.44; low energy: HR = 1.27, 95% CI: 1.10-1.46). Models had similar discrimination (p > 0.14 for all). Perceived fatigability was associated with mortality risk among participants free of arthritis or osteoarthritis who otherwise appeared healthy (no arthritis: HR = 1.45, 95% CI: 1.15-1.84; arthritis: HR = 1.09, 95% CI: 0.92-1.30; p-interaction = 0.031). Unusual tiredness was associated with mortality among those with a history of diabetes (no diabetes: HR = 1.16, 95% CI: 0.97-1.38; diabetes: HR = 1.65, 95% CI: 1.22-2.23; p-interaction = 0.045) or pulmonary disease (no pulmonary disease: HR = 1.22, 95% CI: 1.05-1.43; pulmonary disease: HR = 2.15, 95% CI: 1.15-4.03; p-interaction = 0.034). Conclusions Higher perceived fatigability and fatigue symptoms were similarly associated with higher all-cause mortality, but utility differed by chronic condition. Perceived fatigability might be useful for health screening and long-term mortality risk assessment for well-functioning adults. Alternatively, self-reported fatigue appears more disease-specific with regards to mortality risk.