A computer implemented method for non-invasively estimating blood flow characteristics to assess the severity of plaque and/or stenotic lesions using contrast distribution predictions and measurements, the method comprising: receiving one or more patient-specific images of at least a portion 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 at points of the patient's vasculature with points of a three-dimensional patient-specific anatomic model of the patient's vasculature generated using the received patient-specific images, by projecting one or more contrast values of the measured distribution of the contrast agent to one or more points in the patient-specific anatomic model, wherein said projecting includes assigning contrast values for each point of a three-dimensional finite element mesh; defining one or more physiological and boundary conditions of a blood flow in the patient-specific anatomic model; simulating (310, 312), using a processor, the distribution of the contrast agent through one or more points of the patient-specific anatomic model using the defined one or more physiological and boundary conditions; comparing, using a processor, 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; updating the defined physiological and boundary conditions, said updating comprising updating the physiological and boundary conditions using one or more of a derivative-free optimization based on nonlinear ensemble filtering, or a gradient-based method that uses finite difference or adjoint approximation; the simulating, comparing and updating being performed iteratively until the similarity condition is satisfied, and each iteration of the simulation being performed using said one or more points of the patient-specific anatomic model and the updated physiological and boundary conditions; and once the similarity condition is satisfied, calculating, using a processor, one or more blood flow characteristics of blood flow through the patient-specific anatomic model based on the updated physiological and boundary conditions; and outputting (318A, 318B, 318C) one or more of: the simulated contrast distribution, the one or more calculated blood flow characteristics, and the patient-specific anatomic model to an electronic storage medium or display. receiving one or more patient-specific images of at least a portion 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 at points of the patient's vasculature with points of a three-dimensional patient-specific anatomic model of the patient's vasculature generated using the received patient-specific images, by projecting one or more contrast values of the measured distribution of the contrast agent to one or more points in the patient-specific anatomic model, wherein said projecting includes assigning contrast values for each point of a three-dimensional finite element mesh; defining one or more physiological and boundary conditions of a blood flow in the patient-specific anatomic model; simulating (310, 312), using a processor, the distribution of the contrast agent through one or more points of the patient-specific anatomic model using the defined one or more physiological and boundary conditions; comparing, using a processor, 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; updating the defined physiological and boundary conditions, said updating comprising updating the physiological and boundary conditions using one or more of a derivative-free optimization based on nonlinear ensemble filtering, or a gradient-based method that uses finite difference or adjoint approximation; the simulating, comparing and updating being performed iteratively until the similarity condition is satisfied, and each iteration of the simulation being performed using said one or more points of the patient-specific anatomic model and the updated physiological and boundary conditions; and once the similarity condition is satisfied, calculating, using a processor, one or more blood flow characteristics of blood flow through the patient-specific anatomic model based on the updated physiological and boundary conditions; and outputting (318A, 318B, 318C) one or more of: the simulated contrast distribution, the one or more calculated blood flow characteristics, and the patient-specific anatomic model to an electronic storage medium or display.