Stroke is the third most common cause of death and one of the most common cause of long-term disability in the Western world. Carotid plaque morphology is the main predictor of cerebrovascular accidents, more than the degree of stenosis.The primary aim was to validate virtual histology- intravascular ultrasound (VH-IVUS) as a diagnostic tool for carotid plaque characterization, by comparison with histology, through ex-vivo evaluation of carotid plaques. The secondary target was to compare VH-IVUS with high-resolution MRI (HR-MRI) through in-vivo evaluation of carotid artery plaques.In the ex-vivo study, data were acquired from six carotid arteries explanted from six symptomatic male patients with a mean age of 72 W 9.64 years. Sectional images obtained with the IVUS catheter were compared with digitalized histological images. Twelve consecutive patients (eight men, four women, mean age of 75 W 6.33 years), candidates for carotid artery stenting, were included in the in-vivo study. All histological and HR-MR images were converted to a digital format and the exact percentages of the four plaque components were determined.Forty-two images were used for correlation between VH-IVUS and histology. Quantitative analysis of different plaque components revealed a good concordance (0.82) between the two methods [95% confidence interval (CI) 0.69-0.92]. Precision rates of VH-IVUS for concordance with true histology of different plaque components were 99.4% for fibrous tissue, 85.9% for fibrolipid tissue, 71.4% for calcium and 83.4% for necrosis. Comparison between HR-MRI and VH-IVUS was performed on 27 images. Concordance between the two methods was 0.84 (95% CI 0.69-0.92). Precision rates were, respectively, 85.3, 95.2, 90.2 and 82.0%.We believe that VH-IVUS may be useful when a quick intraprocedural evaluation of a carotid plaque before or after stent placement is required, but is not suitable for the accurate in-vivo differentiation between stable and unstable plaques prone to rupture, due to the suboptimal assessment of the necrotic component, fibrous cap thickness and rupture signs. We do believe, however, that these results need further evaluation in larger populations to be confirmed.