Background: Surgical site infection (SSI) was the most common complication of tibial plateau fracture after open reduction and internal fixation (ORIF). Severe infections even required repeat surgeries, which would cause serious psychological harm to patients and increased the economic burden of treatment. In order to identify the characteristics of the SSI and to avoid the occurrence of SSI, we conducted a prospective study to investigate the incidence and independent risk factors of SSI after ORIF for closed tibial plateau fractures in adults. Methods: This study was performed at a first-level trauma center. From October 2014 to December 2018, the study subjects were adult patients with closed fractures of the tibial plateau, all of whom underwent open reduction and internal fixation (ORIF) treatment. Finally, a total of 1108 patients were followed up. We collected patient demographics information, surgery-related variables, and indexes from preoperative laboratory examinations. Univariate and multivariate logistic analysis models were used to investigate the potential risk factors. Results: Twenty-five patients (2.3%, 25/1108) developed SSI. A total of 15 of 25 infections (60.0%) were due to Staphylococcus aureus and 3 (12.0%) were due to MRSA. Independent risk factors of SSI identified by multivariate logistic analysis model were bone grafting: autograft (OR 6.38; 95% CI 2.155-18.886; p = 0.001) and allograft (OR 3.215; 95% CI 1.009-10.247; p = 0.048), fracture type (Schartzker V-VI) (OR 8.129; 95% CI 2.961-22.319; p < 0.001), aspartate aminotransferase (>40 U/L) (OR 5.500; 95% CI 2.191-13.807; p < 0.001), white blood cell (>10*10 9 /L) (OR 2.498; 95% CI 1.025-6.092; p = 0.044), and anion gap (>16 mmol/L) (OR 8.194; 95% CI 1.101-60.980). Conclusions: We should pay enough attention to patients who carried one or more of these factors at admission and adopt more reasonable treatment strategies to reduce or avoid the occurrence of SSI.