In 1996, adiponectin was reported to be the most abundant transcript in adipose tissue. Animal studies revealed that administering adiponectin improves insulin resistance and blood glucose levels and inhibits atherosclerosis. In the present article, we review the significance of measuring serum high-molecular-weight (HMW) adiponectin levels in human subjects. Our cross-sectional studies revealed that the serum HMW adiponectin concentration was 1.9 times higher in healthy Japanese females than males and had a strong positive correlation with HDL-cholesterol but a negative correlation with BMI and the homeostasis model assessment insulin resistance index (HOMA-IR). They also indicated that the serum HMW adiponectin concentration had a stronger association with HOMA-IR and metabolic syndrome than the total adiponectin concentration. Our longitudinal study, a 6-year follow-up of Japanese men, suggested that a decreased level of HMW adiponectin is a predictor of progression to metabolic syndrome. In another intervention study, lifestyle modification for 3 months induced a decrease in BMI and waist circumference and an increase in serum HMW adiponectin but not the total adiponectin level in 16 Japanese males with metabolic syndrome. Administering thiazolidinediones to diabetic patients increased the serum HMW adiponectin concentration 3 fold and improved glucose and lipid profiles and blood pressure. Some people may inherit a lower serum concentration of adiponectin, and have a higher risk of developing cardiovascular diseases.It is suggested that HMW adiponectin is a useful marker for the evaluation and care of subjects with metabolic syndrome and related disorders.