Background: EUS-guided biliary drainage (BD) is an evolving alternative technique for patients with malignant biliary obstruction for which ERCP failed. Objective: To compare the outcomes of 2 nonanatomic EUS-guided BD routes: hepaticogastrostomy (HPG) and choledochoduodenostomy (CD). Design: Prospective, randomized trial. Setting: Tertiary endoscopic referral center. Patients: Forty-nine patients with unresectable distal malignant biliary obstruction and failed ERCP were included. The HPG group had 25 patients and the CD group had 24 patients. Interventions: EUS-guided HPG or CD. In all procedures, a biliary puncture with a 19-gauge needle followed by cholangiography, wire advancement, track dilation, and self-expandable metal stent deployment were performed. Main Outcome Measurements: Technical and clinical success, quality of life, adverse events, and survival. Results: The technical success rate was 96% for HPG and 91% for CD. The clinical success rate was 91% for HPG and 77% for CD. The mean procedural time was 47.8 minutes for HPG and 48.8 minutes for CD. The mean scores of quality of life were similar during follow-up. The overall adverse event rate was 16.3% (20% for the HPG group and 12.5% for the CD group). One patient with a bile leak required percutaneous biloma drainage. There was no statistical difference between the 2 techniques and no difference with regard to survival time between the 2 groups. Limitations: Single-center study. Conclusion: HPG and CD techniques are similar in efficacy and safety. Both HPG and CD seem valid alternative options for BD in patients with distal malignant biliary obstruction after failed ERCP.