The present study was designed to investigate the relationship of isoforms of adiponectin to insulin sensitivity in subjects with HIV-associated insulin resistance in response to treatment with the thiazolidinedione, rosiglitazone. The two isoforms of adiponectin, HMW (high-molecular-mass) and LMW (low-molecular-mass), were separated by sucrose-gradient-density centrifugation. The amount of adiponectin in gradient fractions was determined by ELISA. Peripheral insulin sensitivity (Rd) was determined with hyperinsulinaemic-euglycaemic clamp, whereas hepatic sensitivity [HOMA (Homoeostasis Model Assessment) %S] was based on basal glucose and insulin values. Treatment with rosiglitazone for 3 months resulted in a significant improvement in the index of hepatic insulin sensitivity (86.4+/-15% compared with 139+/-23; P=0.007) as well as peripheral insulin sensitivity (4.04+/-0.23 compared with 6.17+/-0.66 mg of glucose/kg of lean body mass per min; P<0.001). Improvement in HOMA was associated with increased levels of HMW adiponectin (r=0.541, P=0.045), but not LMW adiponectin. The present study suggests that the HMW isoform of adiponectin is important in the regulation of rosiglitazone-mediated improvement in insulin sensitivity in individuals with HIV-associated insulin resistance, particularly in the liver.