OBJECTIVE We used intravascular ultrasound (IVUS) and virtual histology (VH) to assess the differences of plaque burden and composition between target coronary arteries containing the culprit lesion and non-target coronary arteries. METHODS Sixty patients referred for acute (n = 19) or elective (n = 41) coronary angiography were included. The target vessel containing the culprit lesion was identified by angiography. A non-target coronary artery was chosen for comparison. The first 4 cm of each vessel were analyzed with IVUS and VH. RESULTS Total plaque burden was higher in the target vessel compared to the non-target vessel (52.4% vs. 45.9%, a relative difference of 14.2%; p < 0.001). The plaque composition of the target vessel correlated strongly with the plaque composition of the non-target vessel, but the relative amount of necrotic core was significantly higher in the target vessels (21.7% vs 19.2%; p = 0.028), whereas the amount of fibrolipidic material was significantly greater in non-target vessels (10.6% vs. 12.7%; p = 0.035). CONCLUSIONS We conclude that in patients with relevant coronary artery disease, plaque burden and the amount of necrotic core material are greater in the target vessel. There is a strong correlation of plaque composition between target and non-target coronary arteries.