BACKGROUND Adiponectin, synthesized by adipocytes, has been shown to be a predictor of type 2 diabetes. Adiponectin circulates in plasma as three oligomeric isoforms. High-molecular-weight (HMW) adiponectin is thought to be the most biologically active form of adiponectin in terms of glucose homeostasis. OBJECTIVE Our objective was to investigate whether HMW adiponectin is more strongly associated with incident diabetes than is total adiponectin. METHODS A nested case-cohort study was conducted in a population-based cohort of 9740 middle-aged, initially healthy, white and African-American participants of the Atherosclerosis Risk in Communities (ARIC) study followed for up to 9 yr. Plasma total and HMW adiponectin were measured by ELISA in 550 incident diabetes cases and 540 noncases. RESULTS Overall hazard ratios (95% confidence intervals) for developing diabetes for those in the fourth (vs. the first) quartile of total adiponectin, HMW adiponectin, and the ratio of HMW to total were 0.40 (0.25-0.64), 0.38 (0.23-0.63), and 0.65 (0.42-0.99), respectively, after adjustment for age, sex, ethnicity, study center, parental history of diabetes, hypertension, body mass index, and waist-to-hip ratio and 0.52 (0.32-0.85), 0.51 (0.31-0.86), and 0.77 (0.50-1.20), respectively, after additional adjustment for inflammation score (a score composed of six inflammation markers) and fasting insulin. When further adjusting for baseline fasting glucose, the graded associations were attenuated substantially and lost their gradation. CONCLUSIONS In this community-based sample of U.S. adults, higher total and HMW adiponectin concentrations were similarly associated with a lower incidence of diabetes over 9 yr of follow-up.