Antiretroviral therapy (ART) is frequently associated with metabolic alterations, including insulin resistance and diabetes mellitus. In this pilot study, we evaluated the effect of the PPARgamma activator troglitazone on ART-associated insulin resistance in HIV-infected patients with ART-associated diabetes mellitus. Six patients with protease inhibitor (PI)-associated diabetes mellitus, lipodystrophy and dyslipidemia were treated with troglitazone 400 mg q.d. for 3 months. Previous oral antidiabetics were discontinued prior to the study. At baseline and after 3 months, insulin sensitivity (intravenous insulin tolerance test), body composition (multifrequence bioelectrical impedance analysis) and fat distribution (CT scan quantification) were assessed. Glycaemic control (fasting and postprandial blood glucose, fructosamine, glycosylated haemoglobin) and serum lipid status were determined monthly. In four of the six patients, there was a clear improvement in insulin sensitivity, resulting in a reversal of insulin resistance in two of these patients. Overall, there was an increase in lean body mass and a decrease in total body fat. The volume of visceral adipose tissue decreased whilst the volume of subcutaneous adipose tissue increased. Total cholesterol, LDL and HDL cholesterol increased, and total triglycerides and VLDL-cholesterol decreased. No adverse effects such as hepatotoxicity were observed. Treatment with troglitazone 400 mg q.d. can ameliorate and in some cases even reverse ART-associated insulin resistance. Therefore, further studies including non-diabetic patients with ART-associated insulin resistance may be helpful in evaluating the long-term effects of thiazolidinediones on ART-associated insulin resistance and other metabolic complications, such as adipose maldistribution and dyslipidaemia.