To identify the potential controllable risk factors for surgical site infection (SSI). A retrospective cohort study. Seven Level-I trauma centers. Patients with OTA/AO 41 B or C tibial plateau fractures (n = 2106). Various surgical treatments for tibial plateau fractures. The primary outcome was SSI after the index operation. The secondary outcomes were the risk factors for SSI, identified using backward stepwise generalized multiple regression analysis. Of the 2106 enrolled patients, 94 had deep SSIs. The average SSI rate was 4.5%. Fracture morphology revealed type B injuries in 57.5% and type C in 42.5% of the patients. Univariate regression analysis revealed that several factors, namely, number of comorbidities [>6 vs. none; odds ratio (OR) 8.01, 95% confidence interval (CI) 2.8-22.8, P < 0.001], diabetes mellitus (OR 3.5, 95% CI 2.0-6.3, P < 0.001), high body mass index (OR 1.3, 95% CI 1.1-1.6, P = 0.001), OTA/AO fracture type C (OR 5.6, 95% CI 3.3-9.5, P < 0.001), compartment syndrome (OR 9.1, 95% CI 5.7-14.8, P < 0.001), and open fracture (OR 6.6, 95% CI 3.7-11.7, P < 0.001), were associated with a significantly higher SSI risk. Analysis of microbial sensitivity tests revealed that 55.1% of the pathogens were resistant to perioperative antibiotic prophylaxis. Most of the identified risk factors cannot be controlled or are subject to other factors that are difficult to control. However, our data suggest that the choice of perioperative antibiotic prophylaxis may influence the rate of SSI. This possibility should be investigated in a prospective randomized controlled trial. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.