Background: Surgical site infections (SSIs) and their prevention continue to be a major point of focus in all surgical specialties today. Antibiotic prophylaxis is one of the mainstays in their prevention. Due to the consistently high proportion of infections caused by intestinal flora from the start of our wound surveillance registry in 2005, we conducted a change in prophylactic antibiotic therapy from cloxacillin in 2012 to trimethoprim/sulfamethoxazole (TMP-SMX) in 2013. Methods: The study included all patients undergoing vascular surgery with groin incisions between March 1 and June 30 in 2012 and 2013, respectively, whereby the antibiotic regime was changed in between the 2 sampling periods. The diagnosis of SSI was based on clinical examination and microbiological results. Results: Two hundred nineteen patients with inguinal incisions were included in the analysis: 105 in the cloxacillin group of which 19% had SSI and 114 in the TMP-SMX group with an SSI rate of 18% (P = .77), without differences between the 2 groups regarding age, gender, proportion of emergency surgery, type of surgery, or frequency of concomitant foot ulcers. The high proportion of infections caused by intestinal flora between time periods was unchanged (67% vs 81%, P = .34). Conclusion: There was no difference between the 2 groups, suggesting that the choice of antibiotic prophylaxis had a limited role in preventing SSI at our center. Despite this, the lower cost and ease of the administration of TMP-SMX can be seen as convincing advantages.