Introduction The reported incidence of infection related with tibial plateau fractures (IRTPF) ranges from 2 to 23%. This complication can result in catastrophic consequences such as deformity, post-traumatic osteoarthritis, chronic pain, loss of function, and substantial economic burdens on healthcare systems due to extended hospital stays and the resources required for treatment. Consequently, it is imperative to emphasize the identification of infection risk factors. Methods A retrospective case-control study was designed, encompassing patients who underwent surgery for tibial plateau fractures between 2015 and 2020. Frequencies and measures of central tendency were compared between infected patients (cases) and non-infected patients (controls) using rank-based statistical tests. Subsequently, two logistic regression models were employed to control for potential confounding variables. Results A total of 314 patients were included, predominantly male (71.15%). Average age of 44.41 years. IRTPF were observed in 7.64% of the patients. In the univariate inferential statistical analysis, high-energy fractures (OR 6.35, p < 0.001), fractures with compartment syndrome (OR 7.10, p < 0.001), two-stage management with temporary external fixation (OR 8.18, p < 0.001), the use of 2 or more approaches in definitive surgery (OR 2.93, p = 0.011), and the use of two or more plates (OR 9.17, p < 0.001) were identified as risk factors for infection. On average, the duration of surgery in infected patients was 201.2 min, compared to 148.4 min in non-infected patients (p < 0.001). When performing two logistic regression models, the following independent risk factors were identified: high-energy fractures (OR 5.04, p = 0.012), the presence of compartment syndrome (OR 4.53, p = 0.007), and the use of two or more plates in definitive surgery (OR 5.04, p = 0.023). Conclusions High-energy tibial plateau fractures (Schatzker IV, V, and VI), the presence of concomitant compartment syndrome, and the use of 2 or more plates in definitive surgery are associated with a higher risk of infection related to fracture following open reduction and osteosynthesis treatment.