An in-vivo feasibility study of potentially improved atherosclerosis CT imaging is presented. By administration of two different contrast agents to rabbits with induced atherosclerotic plaques we aim at identifying both soft plaque and vessel lumen simultaneously. Initial injection of iodinated nanoparticle (INP) contrast agent (N1177 - Nanoscan Imaging), two to four hours before scan, leads to its later accumulation in macrophage-rich soft plaque, while a second gadolinium contrast agent (Magnevist) injected immediately prior to the scan blends with the aortic blood. The distinction between the two agents in a single scan is achieved with a double-layer dual-energy MDCT (Philips Healthcare) following material separation analysis using the reconstructed images of the different x-ray spectra. A single contrast agent injection scan, where only INP was injected two hours prior to the scan, was compared to a double-contrast scan taken four hours after INP injection and immediately after gadolinium injection. On the single contrast agent scan we observed along the aorta walls, localized iodine accumulation which can point on INP uptake by atherosclerotic plaque. In the double-contrast scan the gadolinium contributes a clearer depiction of the vessel lumen in addition to the lasting INP presence. The material separation shows a good correlation to the pathologies inferred from the conventional CT images of the two different scans while performing only a single scan prevents miss-registration problems and reduces radiation dose. These results suggest that a double-contrast dual-energy CT may be used for advanced clinical diagnostic applications.