Cardiovascular risk factors such as elevated serum lipid levels are important in the development of coronary atherosclerosis. Radiofrequency (RF) analysis of intravascular ultrasound [IVUS, Virtual histology (TM) (VH)] offers a unique tool to study the composition of coronary atherosclerotic plaque in vivo. We used data from the multicentre VH registry to assess the association between cardiovascular risk factors and coronary plaque volume and composition. Between August 2004 and July 2006, 990 patients in 42 centres were enrolled in a prospective, multicentre, non-randomized global VH registry. Coronary artery imaging was performed by conventional IVUS and RF-IVUS. The four RF-IVUS plaque components [dense calcium (DC), necrotic core (NC), fibrous (F) tissue, and fibro fatty (FF)] were analysed in every recorded frame. The results were expressed as mean cross-sectional areas, absolute volume, and percentage of total plaque volume. Risk factor assessment included evaluation of family history of previous myocardial infarction (MI), past or current smoking, diabetes mellitus, hypertension, and the laboratory measurements. Patients with diabetes had an increased relative proportion of NC (6.47 +/- 0.28 vs. 5.86 +/- 0.14%, P = 0.037) and DC (4.58 +/- 0.27 vs. 3.90 +/- 0.14%, P = 0.017), and patients with hypertension had an increased relative proportion of FF, DC (4.35 +/- 0.16 vs. 3.57 +/- 0.17%, P = 0.02) and NC (6.24 +/- 0.17 vs. 5.60 +/- 0.19%, P = 0.01). Compared with patients with LDL-C < 100 mg/dL, patients with LDL-C > 160 mg/dL had higher plaque volume (342.1 +/- 26.2 vs. 318.6 +/- 10.7 mm(3)). Linear regression analysis showed a correlation between the level of HDL-C and F (r = -0.149, P < 0.01), FF (r = -0.106, P < 0.01), and NC (r = -0.90, P < 0.05). The level of LDL correlated with F (r = 0.110, P < 0.01). Patients with prior MI have an increased percentage of F (30.03 +/- 0.59 vs. 28.20 +/- 0.37%, P = 0.009). Smoking had no relevant effect on plaque composition. Treatment with acetylsalicylacid and statins reduced FF with altering plaque volume. Radiofrequency-IVUS detects marked differences in coronary plaque composition related to the risk factor profile with particular focus on lipid levels. Greater amounts of NC were associated with diabetes, hypertension, MI, and low HDL-C. The effects of treatment of changes related to plaque composition are underway.