The aim of this study was to prospectively evaluate the morphological characteristics of culprit coronary lesions according to clinical presentation. A combined, comprehensive, multi-imaging modality protocol was systematically used. A total of 46 consecutive patients with stable angina (n = 24) or acute coronary syndromes (n = 22) were included. Culprit lesions were prospectively studied with angiography, multislice computed tomography (MSCT), intravascular ultrasound and virtual histology. MSCT showed a lower radiographic density and a higher remodeling index in culprit lesions of patients with acute coronary syndromes. Intravascular ultrasound examination demonstrated a larger remodeling index, a lower degree of calcification and a higher prevalence of soft lesions in unstable patients. Virtual histology analysis showed a lower percentage of calcium in the area of greatest stenosis and a higher prevalence of lesions with vulnerable characteristics in unstable patients. In multivariable logistic regression analysis, remodeling index by intravascular ultrasound and radiographic density in MSCT were the only independent predictors for identifying unstable culprit lesions. Our study adds further evidence on the best morphological criteria of instability in culprit lesions. Remodeling index by IVUS and low radiographic density by MSTC were the only independent predictors of unstable lesions.