BACKGROUND: The metabolic effects of adiponectin, including insulin sensitivity, seem to become stronger with increasing adiposity. Adiposity may also affect the relationship of adiponectin concentrations with serum lipid profile; markers of inflammation, atherosclerosis, and endothelial function; and ectopic fat accumulation. METHODS: We measured plasma adiponectin concentrations, serum lipids, and serum markers of inflammation, atherosclerosis, and endothelial function in 242 Caucasians without type 2 diabetes. We also measured visceral adipose tissue with magnetic resonance tomography and liver and intramyocellular fat with (1)H magnetic resonance spectroscopy. RESULTS: We divided the study participants into 2 groups: lean [mean (SE) total body fat, 26% (0.6%); n = 119] and obese [36% (0.6%); n = 123]. In the obese group, plasma adiponectin concentrations showed a strong positive association with concentrations of HDL cholesterol (P <0.0001) and negative associations with LDL cholesterol, triglycerides, high-sensitivity C-reactive protein, interleukin 6, apolipoprotein B(100), soluble E-selectin, soluble vascular cellular adhesion molecule 1, plasminogen activator inhibitor 1, leukocyte count, and liver and intramyocellular fat (all P <0.03). In the lean group, adiponectin showed a less strong association with HDL cholesterol (P = 0.005) and liver fat (P = 0.03) and no significant associations with the other variables (all P >0.10). High visceral adipose tissue was a strong predictor of low adiponectin concentrations, particularly in the obese group, and attenuated many of the significant relationships. CONCLUSIONS: High adiponectin plasma concentrations are associated with favorable lipid profiles, decreased subclinical inflammation, decreased markers of atherosclerosis and endothelial function, and low ectopic fat accumulation, particularly in obese persons. Adiponectin may also have a concentration-related effect on the relationship between visceral adipose tissue and these metabolic characteristics, especially in obese persons.