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Background: The aim of this study was to compare the impact of three different types of intraoperative antibiotic prophylaxis on the risk of postoperative surgical site infection (SSI). Material and Methods: Single-center retrospective cohort study. Patients who underwent surgery for osteosynthesis of a tibial plateau fracture (January 2009–November 2018) in Hospital Clinic i Provincial de Barcelona were included. Three types of prophylaxis during the study period were used: group A (cefuroxime single-dose treatment), group B (meropenem + teicoplanin), and group C (ceftriaxone + teicoplanin). Demographics, co-morbidity, type of fracture, need for external fixation, microbiology data, surgical time, and outcome were recorded. Failure was defined as the need for reintervention due to postoperative surgical site infection. Results: From a total of 148 patients included, 20 cases developed SSI, 8 from group A, 8 from group B, and 4 from group C. Higher ASA scores, Schatzker II classification, need for external fixation, and a prolonged surgical time were associated with a significantly (p < 0.005) increased incidence of SSI. Group C showed the overall highest survival and lowest cumulative risk, but differences were not statistically significant. Conclusions: Group C showed the lowest incidence of infection in this sample. It is necessary to confirm these findings with larger studies. [ABSTRACT FROM AUTHOR]