This paper presents a novel image-guided robot-based system to assist orthopedic surgeons in performing distal locking of long bone intramedullary nails. The system consists of a bone-mounted miniature robot fitted with a drill guide that provides rigid mechanical guidance for hand-held drilling of the distal screws’ pilot holes. The robot is automatically positioned so that the drill guide and nail distal locking axes coincide, using a single fluoroscopic X-ray image. Since the robot is rigidly attached to the intramedullary nail or bone, no leg immobilization or real-time tracking is required. We describe the system and protocol and present a method for accurate and robust drill guide and nail hole localization and registration. The in vitro system accuracy experiments for fronto-parallel viewing show a mean angular error of 1.3/spl deg/ (std=0.4/spl deg/) between the computed drill guide axes and the actual locking holes axes, and a mean 3.0 mm error (std=1.1mm) in the entry and exit drill point, which is adequate for successfully locking the nail.