The aims of the present study are to investigate the effect of glimepiride 1 mg/d on plasma adiponectin and to assess the contribution of adiponectin in changing high-density lipoprotein cholesterol (HDL-c) levels after glimepiride treatment. Forty patients with type 2 diabetes mellitus were included. Plasma adiponectin, fasting plasma glucose, insulin, hemoglobin A(1c), and cholesterol were measured at study entry and after 3 months of treatment with glimepiride. Both plasma adiponectin level (7.5 +/- 4.5 vs 8.3 +/- 4.5 microg/mL, P = .040) and HDL-c level increased significantly (50 +/- 11 vs 53 +/- 10 mg/dL, P = .041) in the all-subjects group. In the low-adiponectin group (initial plasma adiponectin level <6 microg/mL), both plasma adiponectin level (4.5 +/- 0.9 vs 5.9 +/- 2.0 microg/mL, P = .004) and HDL-c level increased significantly (44 +/- 8 vs 49 +/- 9 mg/dL, P = .011). There was no significant change in the high-adiponectin group (initial plasma adiponectin level >or=6 microg/mL). Change in plasma adiponectin level was an independent factor for change in HDL-c level after adjustment for other factors (beta = .574, P = .009, R(2) = 0.524, P = .036). In conclusion, glimepiride improved plasma adiponectin level, especially in the subjects with type 2 diabetes mellitus with low adiponectin level before treatment, and may directly contribute to improving HDL-c level.