Introduction : Surgical site infection (SSI) after pancreatoduodenectomy (PD) is a significant concern. Targeted antibiotic prophylaxis (pAP) has been tested to mitigate antibiotic resistance patterns, especially after preoperative bile duct stenting. The aim of this study was to investigate the effect of enhanced anti-infective prophylaxis (EAP) on the incidence of superficial and intraabdominal SSI. Methods: All patients who underwent PD at a single centre between May 2018 and May 2021 were retrospectively analysed. A control cohort of patients who received pAP with intravenous cefuroxime and metronidazole and routine intraoperative abdominal lavage according to the surgeons’ preferences. Since March 2020, pAP has been changed to piperacillin/tazobactam according to local resistance patterns and combined with routine intraoperative extended abdominal lavage (EIPL). Preoperative selective decontamination of the digestive tract (SDD) has been applied routinely since Jan 2019. Results: In total, 163 patients were included. The standard (n = 100) and EAP (n = 63) groups did not significantly differ with regard to pertinent patient and operative characteristics. In the EAP group, the rates of SSI (14% vs. 37%, p = 0.002, total rate: 28%) and urinary tract infection (24% vs. 8%, p = 0.011, total rate 18%) were significantly lower. Other septic complications were not significantly different. In addition, the risk of developing gastrointestinal bleeding and delayed gastric emptying was significantly lower in the EAP group. Multivariate analysis showed that an age > 67 years was a significant risk factor for SSI. Conclusion: The results indicate that enhanced anti-infective prophylaxis may significantly decrease the incidence of SSI in patients after PD.