A system and method for determining stenosis severity in a subject's vasculature using multi-energy computer tomography (MECT) imaging is provided. In some aspects, the method includes acquiring MECT data using a CT system, performing a material decomposition process on acquired MECT data to generate one or more material density maps, and selecting, using the one or more material density maps, one or more regions of interest (ROIs) encompassing at least one vessel cross-section. The method also includes measuring an iodine content in the one or more ROIs, and determining a stenosis severity based on the measured iodine content. The method further includes generating a report indicating the stenosis severity associated with the subject's vasculature.