Objective-Patients with highly active antiretroviral therapy-associated lipodystrophy (HAARTϩLDϩ) have high plasminogen activator inhibitor-1 (PAI-1) concentrations for unknown reasons. We determined whether (1) plasma PAI-1 antigen concentrations are related to liver fat content (LFAT) independently of the size of other fat depots and (2) rosiglitazone decreases PAI-1 and LFAT in these patients. Methods and Results-In the cross-sectional study, 3 groups were investigated: 30 HIV-positive patients with HAARTϩLDϩ, 13 HIV-positive patients without lipodystrophy (HAARTϩLDϪ), and 15 HIV-negative subjects (HIVϪ). In the treatment study, the HAARTϩLDϩ group received either rosiglitazone (8 mg, nϭ15) or placebo (nϭ15) for 24 weeks. Plasma PAI-1 was increased in HAARTϩLDϩ (28Ϯ2 ng/mL) compared with the HAARTϩLDϪ (18Ϯ3, PϽ0.02) and HIVϪ (10Ϯ3, PϽ0.001) groups. LFAT was higher in HAARTϩLDϩ (7.6Ϯ1.7%) than in the HAARTϩLDϪ (2.1Ϯ1.1%, PϽ0.001) and HIVϪ (3.6Ϯ1.2%, PϽ0.05) groups. Within the HAARTϩLDϩ group, plasma PAI-1 was correlated with LFAT (rϭ0.49, PϽ0.01) but not with subcutaneous or intra-abdominal fat or serum insulin or triglycerides. In subcutaneous adipose tissue, PAI-1 mRNA was 2-to 3-fold higher in the HAARTϩLDϩ group than in either the HAARTϩLDϪ or HIVϪ group. Rosiglitazone decreased LFAT, serum insulin, and plasma PAI-1 and increased serum triglycerides but had no effect on intra-abdominal or subcutaneous fat mass or PAI-1 mRNA. Conclusions-Plasma PAI-1 concentrations are increased in direct proportion to LFAT in HAARTϩLDϩ patients.Rosiglitazone decreases LFAT, serum insulin, and plasma PAI-1 without changing the size of other fat depots or PAI-1 mRNA in subcutaneous fat. These data suggest that liver fat contributes to plasma PAI-1 concentrations in these patients.