There are controversies about the benefits of prophylactic antibiotics in the prevention of postoperative surgical site infection (SSI) in mesh herniorrhaphy for a long time. This study aimed to evaluate the effectiveness and efficacy of systemic prophylactic cefazolin in prevention of wound infection in various types of hernia repair with mesh materials. This is a prospective randomized control study. We evaluated wound infection rates in 395 patients with various kinds of hernia who underwent elective mesh repair using polypropylene mesh from 2007 to 2011. A total of 237 (60.0%) patients received prophylactic cefazolin (study group) and the remaining 158 (40.0%) patients did not receive any prophylactic antibiotics (control group). Patients were followed for infection at the following periods after the operation by an independent surgeon: 10 days, 30 days, 12 months, and then annually for at least 2 years. Eight (2.03%) patients had infection in the site of surgery [2 (1.27%) in the control group and 6 (2.53%) in the study group]. The distribution of infection was not significantly different between the two groups (p = 0.364). The superficial infections were managed by drainage and irrigation. One patient from the study group developed deep SSI and was readmitted and subsequently received antibiotic therapy, drainage, and debridement. Preoperative administration of single-dose cefazolin for prosthetic hernia repairs did not markedly decrease the risk of wound infection. Our results do not support the use of cefazolin as a prophylactic antibiotic for various kinds of abdominal wall hernia repair with mesh