Background Early infections are common during the first month after liver transplantation (LT), whereas no consensus exists on the optimal prophylactic antimicrobial therapy. We aimed to evaluate the effectiveness of cefazolin perioperative prophylaxis in LT. Patients and methods We documented our experience with single-dose cefazolin as prophylaxis for LT. Infections occurring within 30 days following LT during 2006-2015 were documented retrospectively. Univariate and multivariate analyses of risk factors for infection were carried out. Results Among 113 LT recipients receiving cefazolin as prophylaxis, infections occurred in 50 (44%) patients, including surgical site infections (n=24, 21%) and bacteremia (n=14, 12%). Bacteria resistant to cefazolin were documented in 59/72 (82%) isolates. Enterococcal infections were documented in 6% (7/113). Almost half of the infections (44%) occurred in the first week following LT and the vast majority within 2 weeks. The 30-day mortality rate (7%, 8/113) was significantly higher among infected patients (7/50, 14% vs. 1/63, 1.6%, P=0.011). Model for End-stage Liver Disease score, age, and requirement for at least 5 U of packed red cells during transplantation were predictive for postoperative infections. Conclusion In our center, cefazolin was insufficient as perioperative prophylaxis in LT. We suggest that all LT recipients should receive antibiotic prophylaxis targeting microorganisms on the basis of local bacterial ecology and patterns of resistance irrespective of preoperative or intraoperative risk assessment.