BACKGROUND: Biliary contamination significantly correlates with major comorbidities during pancreatic head resection. Recently, a piperacillin-tazobactam prophylaxis demonstrated a lower rate of infectious complications (IC) and postoperative pancreatic fistula (POPF) in this population. However, bacterial contamination is rare in patients without a preoperative biliary drainage (PBD) and probably could not benefit from this antibiotic. Furthermore, little is known about the role of biliary fungal contamination. METHOD: All retrospective cases undergoing pancreatic head resection with intraoperative biliary sample were included. Postoperative outcomes of patients with a piperacillin-tazobactam-based treatment were compared to cases in which a narrow-spectrum antibiotic was administrated, stratified according to the use of a PBD. The same analysis was repeated for antifungal treatment administration. RESULTS: Among the 205 cases included, PBD was necessary in 127 patients (62%). Broad-spectrum treatment was associated with fewer overall and clinically relevant POPF (p = 0.002 and p = 0.004), overall morbidity (p = 0.044), and overall IC (p = 0.018), but only in the PBD group. Similarly, antifungal treatment was significantly associated with some specific IC only in the PBD group. At multivariable analysis, antifungal therapy in the whole cohort (p = 0.029) and the use of a piperacillin-tazobactam (p = 0.007) treatment in patients with a PBD were independently associated with a reduced risk of a clinically relevant POPF. CONCLUSIONS: A broad-spectrum antibiotic therapy reduces overall morbidity after pancreatic head resection, but only in cases with a history of PBD. Furthermore, the use of an antifungal prophylaxis or therapy should be further investigated in these patients because it may reduce the risk of some IC.