OBJECTIVE The objective of this study was to describe the anatomic variations in the saphenous nerve and risk of direct injury to the saphenous nerve and greater saphenous vein during syndesmotic suture button fixation. METHODS Under fluoroscopic guidance, syndesmotic suture buttons were placed from lateral to medial at 1, 2, and 3 cm above the tibial plafond on 10 below-knee cadaver leg specimens. The distance and position of each button from the greater saphenous vein and saphenous nerve were evaluated. RESULTS The mean distance of the saphenous nerve to the suture buttons at 1, 2, and 3 cm were 7.1 ± 5.6, 6.5 ± 4.6, and 6.1 ± 4.2, respectively. Respective rate of nerve compression was as follows, 20% at 1 cm, 20% at 2 cm, and 10% at 3 cm. Mean distance of the greater saphenous vein from the suture buttons at 1, 2, and 3 cm was 8.6 ± 7.1, 9.1 ± 5.3, and 7.9 ± 4.9 mm, respectively. Respective rate of vein compression was 20%, 10%, and 10%. A single nerve branch was identified in 7 specimens, and 2 branches were identified in 3 specimens. CONCLUSIONS There was at least one case of injury to the saphenous vein and nerve at every level of button insertion at a rate of 10% to 20%. Neurovascular injury may occur despite vigilant use of fluoroscopy and adequate surgical technique. Further investigation into the use of direct medial visualization of these high-risk structures should be done to minimize the risk. Levels of Evidence: Therapeutic, Level II: Prospective, comparative study.