Visceral adipose tissue (VAT) is a key pathogenic fat depot in the metabolic syndrome (MetS), but liver fat (LF) may also play an important role. We evaluated associations of VAT and LF with MetS in normal weight, overweight, and obese men and women (BMI = 30 kg/m(2), respectively). This analysis included 2,495 participants from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik study with computed tomography measurements for VAT and LF. MetS was defined by >= 3 of the following: larger abdominal circumference, hypertension, elevated triglyceride (TG), low high-density lipoprotein (HDL), impaired fasting glucose (IFG), and microalbuminuria. We estimated the odds of MetS per 1-s.d. increase in VAT and LF, adjusting for key covariates. VAT was associated with an increased odds of MetS in normal weight, overweight, and obese women (odds ratios (OR) = 2.78, 1.63, and 1.43, respectively; all P <0.01) that diminished in magnitude with increasing BMI (VAT x BMI class interaction P <0.001). In men, VAT was related to MetS only among the overweight (OR = 1.69, P <0.01). LF was associated with MetS in the overweight and obese groups in women (OR = 1.38 and 1.45; both P <0.001) and in men (OR = 1.38, P = 0.01; and OR = 1.27, P = 0.10), but not in the normal weight groups. These BMI-specific relationships persisted when both fat depots were included in the model. VAT and LF were associated with MetS independently of each other, and these relationships were modified by BMI class such that, VAT was the more important depot at lower levels of obesity and LF at higher levels. Importantly, fatty liver may be a novel metabolic risk factor in overweight and obese individuals.