OBJECTIVES: The purpose of this study was to assess the impact of variations in angulation of clamp placement to hold syndesmotic reduction and how subsequent syndesmotic screw placement affects malreduction of the syndesmosis. We hypothesized that an anatomic syndesmosis reduction cannot be reliably achieved with a clamp alone; and, inaccurate placement of intraoperative clamps and trans-syndesmotic screws after reduction can malreduce the ankle syndesmosis. METHODS: After computed tomography scanning of the intact limbs, 14 cadaver legs were dissected; the syndesmosis was completely disrupted in all. Using planned drill holes, clamps were first placed at 0, 15, and 30 angles from the fibula, then separate posterolateral, followed by lateral, screws were placed. After each intervention, the limb had a computed tomography scan so the fibular reduction could be evaluated precisely. RESULTS: Clamps placed at 15 and 30 significantly displaced the fibula in external rotation and caused significant overcompression of the syndesmosis. Thirty-degree lateral screws caused significant anteromedial displacement, external rotation, and overcompression of the syndesmosis. The 15 posterolateral screws also caused significant external rotation and overcompression of the syndesmosis. CONCLUSIONS: Our study demonstrates that intraoperative clamping and fixation can cause statistically significant malreduction of the syndesmosis. This article should alert clinicians that clamp and screw placement can cause iatrogenic malreduction of the syndesmosis and make them aware that these dangers occur with specific clamp and screw angles in particular.