Provided herein is a medical imaging system that allows for real-time guidance of, for example, catheters for use in interventional procedures. In one arrangement, an imaging system is provided that generate a series of images or frames during a dye injection procedure. The system is operative to automatically detect frames that include dye (bolus frames) and frames that are free of dye (mask frames). The series of images may be registered together to provide a common reference frame and thereby account for motion. Sets of mask frames and bolus frames are averaged together, respectively, to improve signal to noise qualities. A differential image is generated utilizing the average mask and average bolus frames. Contrast of the differential image may be enhanced. The system allows for motion correction, noise reduction and/or enhancement of a differential image in real time.