|Backgrounds and Aim: The efficacy of palliative biliary drainage using bilateral or unilateral self-expandable metal stents (SEMS) for a malignant hilar biliary stricture (MHS) remains controversial. This prospective, randomized, multicenter study investigated whether bilateral drainage using SEMS is superior to unilateral drainage in patients with inoperable MHS.Methods: Patients with inoperable high-grade MHS who underwent palliative endoscopic insertion of bilateral or unilateral SEMS were enrolled. The main outcomes were the rate of primary re-intervention for malfunctioning stents, stent patency, technical and clinical success, adverse events, and survival.Results: A total of 133 pathologically diagnosed patients were randomized to the bilateral group (n=67) or the unilateral group (n=66). The primary technical success rates were 95.5% (64/67) in the bilateral group and 100% (66/66) in the unilateral group, respectively (p=0.244). The clinical success rates were 95.3% (61/64) and 84.9% (56/66), respectively (p=0.047). The primary re-intervention rates based on the per protocol analysis were 42.6% (26/61) in the bilateral group and 60.3% (38/63) in the unilateral group (p=0.049). The median cumulative stent patency duration was 252 days in the bilateral group and 139 days in the unilateral group (log-rank test, p<0.01). Bilateral SEMS was a favorable factor for stent patency (aHR 0.30, 95% CI 0.172-0.521, p<0.001). Survival probability and late adverse events were not different between the two groups. Conclusions: Unilateral and bilateral drainage strategies using SEMS had similar technical success rates, but bilateral drainage resulted in fewer re-interventions and more durable stent patency in patients with inoperable high-grade MHS.