Systems and methods are disclosed for assessing the severity of plaque and/or stenotic lesions using contrast distribution predictions and measurements. One method includes: receiving patient-specific images of a patient's vasculature and a measured distribution of a contrast agent delivered through the patient's vasculature; associating the measured distribution of the contrast agent with a patient-specific anatomic model of the patients vasculature; defining physiological and boundary conditions of a blood flow model of the patient's blood flow and pressure; simulating the distribution of the contrast agent through the patient-specific anatomic model; comparing the measured distribution of the contrast agent and the simulated distribution of the contrast agent through the patient-specific anatomic model to determine whether a similarity condition is satisfied; and updating the defined physiological and boundary conditions and re-simulating distribution of the contrast agent through the one or more points of the patient-specific anatomic model until the similarity condition is satisfied.