The appropriate duration of surgical antibiotic prophylaxis in orthotopic liver transplantation (OLT) in the presence of significant iatrogenic immunosuppression is unclear. We hypothesized that 72 hours of perioperative antibiotic prophylaxis would decrease rates of surgical site infection (SSI) in OLT patients when compared with intraoperative antibiotic prophylaxis alone. OLT recipients were randomized to receive either intraoperative antibiotics only (short antibiotics [SAs]) or 72 hours of perioperative antibiotics (extended antibiotics [EAs]). A total of 102 patients were randomized: 51 to the EA group and 51 to the SA group. Rates of SSI and nosocomial infection (NI) in the SA group were 19% and 17%, respectively, compared with 27% (SSI; P = 0.36) and 22% (NI; P = 0.47) in the EA group, although these differences were not statistically significant. Intensive care unit (ICU) length of stay (LOS), hospital LOS, 30-day mortality, and time to infection were also similar between the 2 groups. Patients developing infections had longer ICU LOS and hospital LOS and a higher association with reoperation, endoscopic retrograde cholangiopancreatography, and 30-day readmission. In conclusion, extending perioperative antibiotics to 72 hours from intraoperative dosing alone in OLT patients does not appear to decrease the incidence of SSI or NI. The results from this pilot trial with 60% power suggest that it is acceptable for OLT recipients to receive intraoperative antibiotic prophylaxis alone.