Following cardiac transplantation, accelerated coronary disease limits long-term survival. Because statins may reduce the progression of the disease in part by their anti-inflammatory effects, this study was designed to assess if atorvastatin prevented neointimal hyperplasia and endothelial dysfunction independently of baseline cholesterol levels. Patients were randomized to usual therapy (n = 13) or to 10 to 20 mg of atorvastatin (n = 12). Control subjects received niacin when their low-density lipoprotein (LDL) cholesterol levels were >130 mg/dl (n = 4). Neointimal hyperplasia by intracoronary ultrasonography, endothelial dependent vascular reactivity, and coronary flow reserve were measured at baseline and 1 year. Control group total cholesterol (203 +/- 11 to 200 +/- 13 mg/dl) and LDL (116 +/- 10 to 119 +/- 11 mg/dl) remained stable, whereas there was a nonsignificant reduction at 12 months in the atorvastatin group (total cholesterol 216 +/- 28 to 178 +/- 21 mg/dl; LDL 126 +/- 17 to 100 +/- 18 mg/dl). At 2 to 3 months there was a significant increase in total cholesterol and LDL cholesterol that was reduced with atorvastatin. At 1 year, patients taking atorvastatin showed a decrease in new or progressing lesions (2.5 +/- 1.7 vs 4.2 +/- 1.8 lesions/patient, p = 0.02), progression of maximal intimal thickness (0.12 +/- 0.07 vs 0.52 +/- 0.17 mm, p = 0.04), and percent area stenosis (5.9 +/- 2.2% vs 19.0 +/- 5.5%, p = 0.04). Atorvastatin ameliorated progressive endothelial dysfunction, whereas coronary flow reserve was unchanged in both groups. Atorvastatin administered to patients with normal or mild hypercholesterolemia in the initial year after transplant reduced the initial increase in LDL cholesterol, and, by doing so, prevented the development and progression of coronary artery lesions and endothelial dysfunction with only mild long-term decreases in cholesterol levels.