Background: A standard protocol for the management of syndesmosis injuries has yet to be established. Debate persists regarding number of screws, screw diameter, number of cortices purchased, and the need for and timing of screw removal. The purpose of this study was to identify factors related to screw fixation that may lead to the ultimate failure of syndesmosis fixation defined as a loss of reduction of the syndesmosis, screw breakage, screw loosening, or widening of the medial clear space. Materials and Methods: A retrospective assessment of 137 consecutive patients who underwent open reduction and internal fixation of the distal tibiofibular joint at a single institution from 2004 to 2008 was performed. Clinical and radiographic data were recorded regarding problems with questionable clinical significance (number of syndesmotic screws, number of cortices, screw diameter, screw location, hardware failure) and loss of syndesmosis reduction. A series of Fisher's exact tests were used to evaluate outcomes. A p value of 0.05 defined as significant. Results: The 3.5-mm diameter screws were statistically more likely to break than 4- or 4.5-mm screws, but there was no difference in frequency of loss of reduction of the syndesmosis as a function of screw diameter; however, a power study revealed an n value of 1656 would be required to show a significant difference. Conclusion: Screw diameter may have an effect on screw breakage but clinical significance of hardware failure itself is unknown including whether or not it results in a loss of reduction or failure of syndesmotic fixation. Level of Evidence: III, Retrospective Comparative Study