OBJECTIVES: To determine the risk factors for deep infection in OTA/AO 43C pilon fractures. DESIGN: Retrospective, case-control study. SETTING: Single institution, Level 1 trauma center. PARTICIPANTS: All patients with 43C pilon fractures treated over a 5-year period with follow-up to bony union. One hundred fifty of 169 of identified patients met inclusion criteria. INTERVENTION: Operative treatment of tibial pilon fracture. MAIN OUTCOME MEASUREMENTS: Deep infection; patient demographics, Gustilo-Anderson classification, location of open fracture wounds, surgical approaches. RESULTS: The overall rate of deep infection was 16.7%. Body mass index, tobacco use, and diabetes were not associated with deep infection. The rate of Gustilo-Anderson type 3A and 3B fractures was significantly higher in those with infection, but the overall open fracture rate was not significantly different between the groups. Medial and anterior open fracture wound location was significantly associated with deep infection, whereas lateral open fracture wound location was not. In closed fractures, anteromedial and anterolateral approaches were not significantly associated with infection, but posterolateral approach was associated with deep infection. Segmental bone loss and the need for soft tissue coverage were the only independent risk factors for deep infection. CONCLUSIONS: High-grade open pilon fractures are at risk of deep infection, and medial/anterior open fracture wounds are particularly vulnerable to developing deep infection. The anteromedial/anterolateral surgical approaches should be selected based on a complete understanding of the fracture pattern and soft tissue injury; however, the posterolateral approach to the tibia should be used with some caution. Ultimately injury factors (segmental bone loss and need for soft tissue coverage) seem to be the most important variables in driving deep infection, and a complete understanding of the bone and soft tissue injury is needed to manage these injuries effectively. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.