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Introduction Despite advancements in pancreatic surgery, postoperative infections—particularly surgical site infections (SSIs), which occur in 6–17% of cases—continue to be a leading cause of morbidity. Effective perioperative antibiotic prophylaxis is essential, though the optimal regimen remains unclear. Recent studies indicate that broad-spectrum antibiotics may be more effective than cephalosporins; however, agents like piperacillin/tazobactam, despite broader coverage, pose risks of resistance development and increased costs.Methods and analysis The PERIoperative antibiotic prophylaxis in PANCreatic surgery (PeriPANC) study is a single-centre, prospective, observational study investigating the effectiveness of piperacillin/tazobactam for perioperative antibiotic prophylaxis in pancreatic surgery, compared with a retrospective cohort previously treated with ampicillin/sulbactam. Around 300 adult patients undergoing pancreatic resection will be included. The primary outcome is the incidence of SSI; secondary outcomes include other infectious complications, microbial resistance and healthcare utilisation. Differences between groups will be analysed with analysis of covariance.Ethics and dissemination The PeriPANC study has been reviewed and approved by the local ethics committee of Heidelberg University Hospital (S-087/2025). As all patients receive standard care and no additional data are collected beyond routine documentation, informed consent is not required. Findings will be disseminated through peer-reviewed publications. The results are expected to inform clinical practice and guideline development in the field of perioperative infection prevention in pancreatic surgery.Trial registration number German Clinical Trials Register (DRKS): DRKS00036546.