BACKGROUND AND OBJECTIVES: Hypercholesterolemia is a key factor in the development of atherosclerosis. We sought to evaluate the relation between hypercholesterolemia and plaque composition in patients with coronary artery disease. SUBJECTS AND METHODS: Study subjects consisted of 323 patients (mean 61.5 years, 226 males) who underwent coronary angiography and virtual histology-intravascular ultrasound examination. Patients were divided into two groups according to total cholesterol level: hypercholesterolemic group (> or =200 mg/dL, n=114) and normocholesterolemic group (<200 mg/dL, n=209). RESULTS: Hypercholesterolemic patients were younger (59.7+/-13.3 years vs. 62.6+/-11.5 years, p=0.036), than normocholesterolemic patients, whereas there were no significant differences in other demographics. Hypercholesterolemic patients had higher corrected necrotic core volume (1.23+/-0.85 mm3/mm vs. 1.02+/-0.80 mm3/mm, p=0.029) as well as percent necrotic core volume (20.5+/-8.5% vs. 18.0+/-9.2%, p=0.016) than normocholesterolemic patients. At the minimal lumen area site, percent necrotic core area (21.4+/-10.5% vs. 18.4+/-11.3%, p=0.019) and necrotic core area (1.63+/-1.09 mm2 vs. 1.40+/-1.20 mm2, p=0.088) were also higher than normocholesterolemic patients. Multivariate linear regression analysis showed that total cholesterol level was an independent factor of percent necrotic core volume in the culprit lesion after being adjusted with age, high density lipoprotein-cholesterol , hypertension, diabetes mellitus, smoking and acute coronary syndrome (beta 0.027, 95% confidence interval 0.02-0.053, p=0.037). CONCLUSION: Hypercholesterolemia was associated with increased necrotic core volume in coronary artery plaque. This study suggests that hypercholesterolemia plays a role in making plaque more complex, which is characterized by a large necrotic core, in coronary artery disease.