Surgical site infection (SSI) is an important cause of morbidity after orthotopic liver transplantation (OLT). Perioperative antibiotic prophylaxis is one of the main modifiable risk factors. We prospectively investigated the epidemiology, risk factors, and prognosis of SSI in a cohort of 167 OLT. Two different schedules of antibiotic SSI prophylaxis were compared. Fifty-six episodes of SSI were included (0.34 episodes/patient). The SSI incidence among patients who received cefazolin and amoxicillin-clavulanate did not differ. Bacteria caused all episodes. The most common pathogen was Escherichia coli (21.25%), among which 47% were extended-spectrum beta-lactamase producers. The only risk factor for SSI was antibiotic therapy before OLT. Patients with SSI had a longer hospital and intensive care unit stay (P<0.05), but survival did not differ. In conclusion, SSI has a high incidence despite antibiotic perioperative prophylaxis; therefore, an integral perspective of SSI and a multifactorial approach other than antimicrobial prophylaxis are needed to prevent it.