The objective of this study was to examine whether the development of cholangitis after preoperative biliary drainage (PBD) can increase the incidence of postoperative pancreatic fistula (POPF). The study population included 185 consecutive patients who underwent pancreaticoduodenectomy from April 2006 to March 2011. All patients were divided into two groups, which consisted of a “no PBD” group (73 patients) and a PBD group (112 patients). Moreover, the PBD group was divided into a “cholangitis” group (21 patients) and a “no cholangitis” group (91 patients). Clinical background, clinical outcome, and postoperative complications were compared between groups. All patients received prophylactic antibiotics using cefmetazole until 1 or 2 days postoperatively. There was no difference between noncholangitis and non-PBD groups except the frequency of overall POPF. Clinically relevant POPF and drain infection occurred in the cholangitis group significantly more than in the noncholangitis group ( P < 0.05). Univariate and multivariate analyses showed that development of preoperative cholangitis after preoperative biliary drainage and small pancreatic duct (less than 3 mm diameter) were independent risk factors for clinically relevant POPF. The frequency of clinically relevant POPF was 8 per cent (eight of 99) in patients without two risk factors, 19 per cent (15 of 80) in patients with one risk factor, and 50 per cent (three of six) in patients with both risk factors. The development of preoperative cholangitis after PBD was closely associated with the development of clinically relevant POPF under the limited use of prophylactic antibiotics.