Deep tissue infection is a serious complication following operative fixation of pilon fractures, yet the influence of intraoperative factors and microbial characteristics remains underexplored. In this retrospective review of 123 patients treated with open reduction and internal fixation, we evaluated demographic, injury-related, operative, and microbiologic variables associated with deep infection. Patients who developed infection had longer operative times than those who did not. This modestly powered study found that operative duration was not independently associated with infection risk after adjustment for key covariates. Larger studies are needed to confirm this finding. Deep infection rates did not differ by surgical approach or time to fixation. Nine patients (7.3%) developed deep infection, with cultures demonstrating a heterogeneous microbial profile most commonly including Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, and Enterobacter cloacae. Deep infections resulted in nonunion in 67% (6/9), PTOA in 44% (4/9), and amputation in 33% (3/9) of cases.