An image data subtraction system suitable for use in Angiography or other medical procedure enhances vessel visualization. The system comprises an imaging system for acquiring, during a medical procedure, data representing multiple temporally sequential individual images of vessels of a portion of patient anatomy. The sequential individual images encompass introduction of a contrast agent. An image processor automatically processes the data representing the multiple temporally sequential individual images to identify a first image indicating presence of the contrast agent and a second image preceding the first image by comparing a difference between measures representative of luminance content of the first and second image, with a threshold. The second image is substantially exclusive of an indication of presence of the contrast agent. The image processor, in response to the difference exceeding the threshold, automatically selects the second image as a mask image and subtracts data representing the mask image from data representing images of the temporally sequential individual images to remove background image detail and emphasize vessel structure in providing processed image data for display. A user interface presents the processed image data for display while the patient is undergoing the medical procedure.