Purpose <p>Proton pump inhibitors (PPIs) are frequently used perioperatively in patients undergoing major liver resection, although their impact on postoperative morbidity remains unclear. This study evaluated the association between preoperative PPI therapy and postoperative complications, particularly biliary leakage.</p> Methods <p>This retrospective single-center cohort study included patients undergoing major liver resection (≥ 4 Couinaud segments) between 2006 and 2024. Patients with and without preoperative PPI therapy were compared regarding postoperative morbidity, assessed using the Comprehensive Complication Index (CCI), and biliary leakage.</p> Results <p>A total of 507 patients were included, of whom 220 (43.4%) received preoperative PPI therapy. Patients receiving PPI therapy had a significantly higher postoperative CCI compared with those without PPI therapy (24.4 ± 25 vs. 17.7 ± 19.7, <i>p</i> = 0.002). Biliary leakage occurred more frequently in the PPI group (38% vs. 26%, <i>p</i> = 0.009), including after propensity score matching. In multivariable logistic regression analysis, preoperative PPI therapy remained independently associated with postoperative biliary leakage (OR 1.95, 95% CI 1.21–3.14; <i>p</i> = 0.006). Microbiological analysis of biliary swabs showed no relevant differences in pathogen profiles between groups.</p> Conclusions <p>Preoperative PPI therapy was associated with increased postoperative morbidity and biliary leakage after major liver resection, even after adjustment for baseline risk factors. Given the observational design, these findings should be considered hypothesis-generating and support careful evaluation of perioperative PPI use in patients without a clear indication.</p> Trial registration <p>The study was registered in the German Clinical Trials Register (application number DRKS00038981).</p> Graphical Abstract <p></p>