AIM: To examine the association between adiposity and mortality in U.S. adults without major cardiovascular risk factors. METHODS: We analyzed 7,948 adults (4,123 women, 3,825 men) aged >
20 years from the National Health and Nutrition Examination Survey (2003-2004, 2011-2016). Participants with cardiovascular disease, estimated glomerular filtration rate <
60 ml/min/1.73m², diabetes, hypertension, or pregnancy were excluded. Adiposity measures, assessed by dual-energy x-ray absorptiometry or anthropometrics, included android and gynoid fat mass index (FMI), android-to-gynoid ratio, subcutaneous, abdominal, and visceral FMI, BMI, and waist circumference. We employed multivariable-adjusted Cox regression and restricted cubic spline models to assess sex-specific associations between adiposity measures and all-cause mortality. RESULTS: Over a median follow-up of 7.8 years, there were 83 deaths among women and 119 among men. In women, BMI, waist circumference, and gynoid FMI showed non-linear associations with all-cause mortality, while in men, BMI, waist circumference, and android-to-gynoid ratio demonstrated similar non-linear associations. In final adjusted models, a 1-SD increase in visceral, subcutaneous, and abdominal FMI among women was associated with 61 % (HR 1.61, 95 % CI 1.17-2.21), 87 % (HR 1.87, 95 % CI 1.13-3.08), and 89 % (HR 1.89, 95 % CI 1.19-2.99) higher mortality risk, respectively. Women in the lowest tertile of gynoid FMI had an 82 % (HR 1.82, 95 % CI 1.01-3.29) higher mortality risk compared to those in the middle tertile. In final adjusted models, a 1-SD increase in gynoid, android, visceral, subcutaneous, and abdominal FMI among men was associated with 30 % (HR 1.30, 95 % CI 1.02-1.65), 41 % (HR 1.41, 95 % CI 1.09-1.83), 54 % (HR 1.54, 95 % CI 1.04-2.28), 69 % (HR 1.69, 95 % CI 1.25-2.29), and 76 % (HR 1.76, 95 % CI 1.25-2.48) higher mortality risk, respectively. Additionally, men in the middle tertile of android-to-gynoid ratio had a 2.68-fold higher mortality risk compared to the lowest tertile, while men in the highest BMI tertile had an 83 % higher mortality risk compared to the lowest tertile. Sex modified the association between gynoid FMI and mortality (P-interaction = 0.008). CONCLUSION: Imaging-based adiposity measures have distinct prognostic value for mortality beyond traditional anthropometrics in adults without cardiovascular risk factors.