Background: Biliary drainage is used to treat jaundice and create an optimal clinical condition prior to liver resection for perihilar cholangiocarcinoma (PHC). The optimal drainage technique is undecided. Methods: This multicenter randomized controlled study compared two drainage approaches in patients with potentially resectable PHC requiring major hepatectomy. Patients with obstructive jaundice and a bilirubin level above 50 μmol/L were randomly assigned to undergo either endoscopic (EBD) or percutaneous transhepatic biliary drainage (PTBD). The primary outcome was the total number of severe preoperative drainage-related complications between randomization and surgery. Results: We enrolled 54 patients; 27 were assigned to EBD and 27 to PTBD. The total number of preoperative drainage-related complications was higher in the PTBD group (52 versus 38) while the percentage of patients with more than one severe complication was comparable between groups (78% versus 81%). The Data Safety Monitoring Board prematurely stopped the study at 50% of accrual because of increased perioperative 90-day mortality in patients who had undergone PTBD (41% versus 7%). Three patients died before surgery (3 PTBD, 0 EBD) and 10 patients died after laparotomy (8 PTBD, 2 EBD). Conclusion: The incidence of preoperative complications following EBD and PTBD was comparable, but PTBD was associated with increased perioperative mortality. Initial EBD is therefore advised in resectable PHC and PTBD only when EBD has failed.