To determine patient-specific and injury-specific factors that may predict infection and other adverse clinical results in the setting of tibial pilon fractures. Retrospective chart review. Level 1 academic trauma center. Two hundred forty-eight patients who underwent operative treatment for tibial pilon fractures between 2010 and 2020. External fixation and/or open reduction and internal fixation. Fracture-related infection rates and specific bacteriology, risk factors associated with development of a fracture-related infection, and predictors of adverse clinical 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). 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. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.