Background: The preoperative biliary drainage (PBD) in ampulla of Vater (AoV) cancer is indiscriminately performed without logical backgrounds. This study was performed to evaluate the effect of PBD on short and long-term outcomes in AoV cancer. Methods: 313 patients who underwent pancreaticoduodenectomy and were pathologically diagnosed as AoV cancer between January 2000 and December 2014 were reviewed. Results: 167 patients (53.4%) underwent PBD: Endoscopic drainage was performed in 106 patients (33.9%) and percutaneous drainage in 61 (19.5%). The postoperative complication rate of PBD group was significantly higher than that of upfront surgery group (48.5% vs. 38.4%, p = 0.045). The 5-year disease-free survival rate (5Y-DFSR) was significantly lower in PBD group compared to upfront surgery group (53.8% vs. 74.3%, p < 0.001). Worse 5Y-DFSR of PBD group was more evident in T1/T2 stage (59.2% vs. 84.1%, p < 0.001). In multivariate analysis with T1/T2 staged patients, PBD was independently associated with worse outcome (hazard ratio 2.145 [95% confidence interval, 1.202–3.826], p = 0.010). Conclusion: For T1/T2 AoV cancer, PBD adversely affected the short-term postoperative complication rate as well as the long-term oncologic outcomes. Therefore, especially in patients with T1/T2 AoV cancer, routine practice of PBD should be refrained and be reserved for selected cases such as cholangitis.