Growing evidence suggests that positive associations between fat mass (FM) and bone mineral density (BMD) are mediated by not only biomechanical but also biochemical factors. Adiponectin is a novel adipocyte-derived hormone that regulates energy homeostasis and has anti-inflammatory and anti-atherogenic effects. Unlike other adipokines such as leptin, adiponectin levels decrease in obesity and type 2 diabetes. The purpose of our study was to investigate associations of serum adiponectin with BMD (DXA and QCT), FM (DXA and QCT), and serum leptin and soluble leptin receptor levels in 38 women and 42 men (age 39-81, BMI 17-55, 86% with type 2 diabetes). After adjusting for age, gender, race, smoking, and diabetes status, serum adiponectin was inversely associated with areal BMD (r = -0.20 to -0.3, all P < 0.01), volumetric BMD (r = -0.35 to -0.44, all P < 0.01), and visceral fat volume (r = -0.30, P < 0.01). These associations remained significant after adjusting for whole body fat mass. The associations of adiponectin with subcutaneous fat volume, whole body FM, and serum leptin level were not significant (all P > 0.1). These data suggest that adiponectin may play a role in the protective effects of visceral fat on BMD.