A prospective controlled clinical study was performed to compare fluoroscopic guidance with fluoroscopy-based surgical navigation for distal locking of intramedullary implants. Forty-two patients with fractures of the lower extremity treated by intramedullary nailing were divided in two groups: distal locking either with fluoroscopic guidance (group I) or with surgical navigation (group II). The average fluoroscopic time to insert one interlocking screw with fluoroscopic guidance was 108 s compared with 7.3s in the navigation group. The average procedure time to insert one interlocking screw in group I was 13.7 min compared with 17.9 min in group II. The drill bit failed to pass through the interlocking hole in one patient from group II. There was no significant difference in the technical reliability between both groups. Fluoroscopic times to achieve equivalent precision are reduced with fluoroscopy-based surgical navigation compared with fluoroscopic guidance. Fluoroscopy-based surgical navigation is recommended for intraoperative guidance in situations where reduction of exposure to radiation is considered advantageous over the increase of procedure time.