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Information on surgical site infection (SSI) after surgical treatment of ankle fracture is limited and remains controversial. The purpose of the present study was to determine the incidence and risk factors for SSI after open reduction and internal fixation (ORIF) of ankle fracture. Patients who underwent ORIF for ankle fracture at 3 centers between January 2015 and December 2016 were included. The potential risk factors for SSI included demographic variables, including age, sex, body mass index (BMI), hypertension, diabetes mellitus, heart disease, smoking, and excessive alcohol intake; blood test variables including preoperative white blood cell count, neutrophil count, red blood cell count, hemoglobin, total protein, albumin and globulin; injury- and surgery-related variables, including duration of operation (minutes), intraoperative blood loss, surgeon level, fracture site, accompanied dislocation, use of a drainage tube, and antibiotic use. Factors related with SSI occurrence were investigated by univariate analysis, and then by multivariate analysis. During hospitalization, 4.37% (66/1511) of patients developed SSI, which was deep in 1.32% (20/1510) and superficial in 3.05% (46/1510). The most common causative agent was polymicrobial (causing approximately half of all SSIs), followed by methicillin-resistant Staphylococcus aureus (MRSA). Multivariate analysis revealed that the significant risk factors for SSI occurrence were open injury, advanced age, incision cleanliness II – IV, high-energy injury, more experienced surgeon level, greater BMI, chronic heart disease, history of allergy, and preoperative neutrophil count > 75%. Preoperative preventative measures should be taken in patients with these conditions to lower the incidence of SSI after ORIF of ankle fracture.LEVEL OF EVIDENCE: Level III - Retrospective Comparative Study.