An X-ray diagnostic imaging system for conducting live fluoroscopic subtraction imaging is described as including an X-ray source for directing X-ray radiation to a patient being examined, an x-ray imaging device positioned for receiving the X-ray radiation and acquiring images in response thereto and a processor arranged in communication with the x-ray source and x-ray imaging device to control acquisition of a contrast-enhanced mask image frame and a live image frame without contrast enhancement, to conduct a pixel shift calculation operation based on a small, user-defined region of interest (ROI), for example, 1/16 of a full frame, to realize a pixel shift vector to correct for motion between live image frames, to shift pixels comprising the mask image frame by pixel shift directions defined by the pixel shift vector, and to subtract the shifted mask image frame from the live image frame to realize a live roadmapping image frame. The system includes a display for displaying the live roadmapping image frame, and a user interface that allows a user to define and capture the small ROI in the displayed image frame for use by the processor conducting the pixel shift calculation.