Objective: To determine patient-specific and injury-specific factors that may predict infection and other adverse clinical results in the setting of tibial pilon fractures. Design: Retrospective chart review. Setting: Level 1 academic trauma center. Patients: Two hundred forty-eight patients who underwent operative treatment for tibial pilon fractures between 2010 and 2020. Intervention: External fixation and/or open reduction and internal fixation. Main Outcome Measurements: Fracture-related infection rates and specific bacteriology, risk factors associated with development of a fracture-related infection, and predictors of adverse clinical results. Results: Two hundred forty-eight patients were enrolled. There was an infection rate of 21%. The 3 most common pathogens cultured were methicillin-resistant Staphylococcus aureus (20.3%), Enterobacter cloacae (16.7%), and methicillin-resistant Staphylococcus aureus (15.5%). There was no significant difference in age, sex, race, body mass index, or smoking status between those who developed an infection and those who did not. Patients with diabetes mellitus (P = 0.0001), open fractures (P = 0.0043), and comminuted fractures (OTA/AO 43C2 and 43C3) (P = 0.0065) were more likely to develop a fracture-related infection. The presence of a polymicrobial infection was positively associated with adverse clinical results (P = 0.006). History of diabetes was also positively associated with adverse results (P = 0.019). Conclusions: History of diabetes and severe fractures, such as those that were open or comminuted fractures, were positively associated with developing a fracture-related infection after the operative fixation of tibial pilon fractures. History of diabetes and presence of a polymicrobial infection were independently associated with adverse clinical results.