A low level of high-density lipoprotein cholesterol (HDL-C) is a risk factor for atherosclerotic disease. Magnetic resonance imaging (MRI) can provide detailed information on carotid atherosclerotic plaque size and composition. The purpose of this study was to correlate HDL levels with carotid plaque burden and composition by MRI. Thirty-four patients with coronary artery disease (CAD) receiving simvastatin plus niacin or placebo for both drugs for three years were randomly selected to undergo MRI of carotid arteries. Atherosclerotic plaque wall volumes (WVs) and plaque components including lipid rich/necrotic core (LR/NC), calcium, fibrous tissue, and loose matrix were measured. Mean WV or atherosclerotic burden was significantly associated with total HDL-C levels (r = -0.39, P = 0.02), HDL(2) (r = -0.36, P = 0.03), HDL(3) (r = -0.34, P = 0.04), and LDL/HDL ratio (r = 0.42, P = 0.02). Plaque lipid composition or LR/NC was significantly associated with HDL(3) (r = -0.68, P = 0.02). Patients with low HDL levels (<or=35 mg/dL) had increased WV (97 +/- 23 vs. 81 +/- 19 mm(3), P = 0.05) compared with patients with HDL levels > 35 mg/dL. Among CAD patients, low HDL-C levels were significantly associated with increased carotid atherosclerotic plaque burden and lipid content by MRI.