HIV-infected patients on antiretroviral therapy frequently develop changes in body fat distribution and disturbances in glucose metabolism, associated with reduced adiponectin levels. Because adiponectin, principally the high-molecular-weight (HMW) form, has insulin-sensitizing properties, we investigated the effects of an increase in adiponectin on glucose metabolism in HIV-lipodystrophy. In this randomized, double-blind, placebo-controlled trial, we included HIV-1-infected patients with severe lipoatrophy, with an undetectable viral load and who had received neither protease inhibitors nor stavudine for ≥6 mo. Patients were randomized to rosiglitazone [8 mg daily (n = 8)] to increase adiponectin levels or placebo (n = 5) for 16 wk. Peripheral glucose disposal, glucose production, and lipolysis were measured after an overnight fast and during a hyperinsulinemic-euglycemic clamp using stable isotopes. Body composition was assessed by computed tomography and dual-energy X-ray absorptiometry. Although body fat distribution was unaffected, rosiglitazone increased total plasma adiponectin levels by 107% (P < 0.02) and the ratio of HMW to total adiponectin by 73% (P < 0.001). In the placebo group, neither total adiponectin levels (P = 0.62) nor the ratio of HMW to total adiponectin changed (P = 0.94). The marked increase in adiponectin induced by rosiglitazone was not associated with significant changes in basal endogenous glucose production (P = 0.90), basal lipolysis (P = 0.90), insulin-mediated suppression of glucose production (P = 0.17) and lipolysis (P = 0.54) nor with changes in peripheral glucose disposal (P = 0.13). Acknowledging the limited statistical power of our small study, these findings, if confirmed by larger studies, could question the importance of adiponectin in regulating glucose metabolism in HIV-lipodystrophy.