BACKGROUND AND OBJECTIVES: Endoscopic retrograde cholangiopancreatography (ERCP) is the primary intervention for malignant distal biliary obstruction (MDBO). However, ERCP may fail for various reasons, requiring alternative interventions such as EUS-guided biliary drainage. Among EUS-guided biliary drainage (EUS-BD) methods, EUS-guided gallbladder drainage (EUS-GBD) is emerging as a viable option for patients who have failed ERCP and EUS-BD. The aim of this study is to evaluate the efficacy and safety of EUS-GBD as salvage therapy for MDBO and its potential role in allowing the initiation of chemotherapy. METHODS: This is a retrospective multicenter study of consecutive patients with MDBO with failed ERCP and/or EUS-BD that subsequently underwent EUS-GBD with lumen-apposing metal stent. RESULTS: Ninety-six patients from 9 centers in Spain were included. Technical success was achieved in 99% of patients, while clinical success, defined as bilirubin reduction <
50% within 14 days after the procedure, was achieved in 78.1% of patients. Bilirubin levels were normalized in 65.6% of patients. The median time to normalization of bilirubin levels was 15 (7-27) days. Related to continuation of oncological treatment, 44/77 (57.1%) eligible patients were able to start chemotherapy after the procedure, and 12/17 (70.6%) eligible patients underwent surgery in the end. Adverse events were observed in 26.3% of cases, with 3 patients requiring surgery and 3 deaths related to EUS-GBD. CONCLUSIONS: EUS-GBD represents a potential alternative to MDBO in cases where ERCP has failed, with an appropriate profile of patients starting chemotherapy. However, in light of the considerable number of adverse events and the moderate efficacy, it may be advisable to consider this approach as a second-line option.