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Trans-syndesmotic screws are commonly used to repair syndesmosis ruptures and stabilize the ankle joint. Just as with any surgery, the neurovascular structures can be compromised, causing complications. We evaluated the position of the perforating branch of the peroneal artery to define the risk of arterial compromise during placement of 2 trans-syndesmotic screws. In 37 cadaveric specimens, 2 trans-syndesmotic screws were inserted 2 and 4 cm proximal to the ankle joint. The distances between the perforating branch of the peroneal artery and the screws and the other anatomic landmarks were measured. Significant differences were calculated between the male and female limbs, and regression analysis was used to determine the significant associations between the tibial length and screw location. The perforating branch of the peroneal artery passed through the interosseous membrane 3.42 ± 0.6 cm proximal to the tibial plafond. The artery was located up to 4 mm from the superior and inferior screws 51.4% and 10.8% of the time, respectively. A greater percentage of male specimens displayed close proximity between the artery and the superior screw, and the distance of the artery from the distal fibula was statistically significant compared with the distance in the female specimens. Regression analysis revealed that the greater the tibial length, the closer the superior screw was to the artery, with a negative correlation discovered for the inferior screw. We concluded that superior screw placement increased the risk of injuring the perforating branch of the peroneal artery injury, and the likelihood of injuring the artery with the inferior screw increased as the length of the tibia decreased.