Abstract Background: Substantially increased lipoprotein lipase (LPL) activity was reported in mice overexpressing adiponectin. METHODS Associations of serum adiponectin with serum preheparin LPL mass (serum LPL), fat mass, and fat distribution and markers of insulin resistance and inflammation were examined in 311 young and 148 middle-aged women. RESULTS In young women, serum adiponectin was positively associated with high-density lipoprotein cholesterol (HDL-C) and serum LPL and inversely with body mass index (BMI), abdominal girth, trunk fat mass, trunk/lower-body fat ratio, serum leptin, and log high-sensitivity C-reactive protein. These associations were confirmed in middle-aged women. Adiponectin showed positive association with the Matsuda insulin sensitivity index and inverse associations with homeostasis model assessment of insulin resistance, serum triglycerides, leukocyte count, interleukin-6, and plasminogen activator inhibitor-1 in middle-aged women but not in young women. Multivariate analysis revealed that serum LPL and trunk/lower-body fat ratio were significant determinants of adiponectin, not only in young women but also in middle-aged women. These associations were independent of markers of inflammation and insulin sensitivity/resistance. CONCLUSIONS LPL mass in preheparin serum was associated with adiponectin levels independently of fat mass and distribution, systemic inflammation, and insulin resistance in healthy women. Therefore, LPL may represent a link between low adiponectin and dyslipidemia found in metabolic syndrome and type 2 diabetes mellitus.