Background: EUS-guided choledoco-duodenostomy using electrocautery-enhanced lumen-apposing metal stents (ECE-LAMS) is becoming the gold standard in case of endoscopic retrograde cholangio-pancreatography failure for distal malignant obstruction. Long-term data in larger samples are lacking. Methods: This was a prospective monocentric study including all patients who underwent EUS-guided choledochoduodenostomy (CDS) between September 2016 and December 2021. The primary endpoint was the rate of biliary obstruction during follow-up. Secondary endpoints were technical and clinical success rates, adverse event rates, and identification of risk factors for biliary obstruction. Results: One hundred and twenty-three EUS-guided CDS using ECE-LAMS were performed at Limoges University Hospital were performed during the study period and included in the study. The main cause of obstruction was pancreatic adenocarcinoma in 91 (74.5%) cases. The technical and clinical success rates were 97.5% and 91%, respectively. Twenty patients (16.3%) suffered from biliary obstructions during a mean follow-up of 242 days. The clinical success rate for endoscopic desobstruction was 80% (16/20). In uni- and multivariate analyses, only the presence of a duodenal stent (odds ratio [OR]: 3.6, 95% confidence interval [CI] 95%: 1.2-10.2; P = 0.018) and a bile duct thinner than 15 mm (OR: 3.9, CI 95%: 1.3-11.7; P = 0.015) were the significant risk factors for biliary obstruction during the follow-up. Conclusion: Obstruction of LAMS occurred in 16.3% of cases during follow-up and endoscopic desobstruction is efficacious in 80% of cases. The presence of duodenal stent and a bile duct thinner than 15 mm are the risk factors of obstruction. Except in these situation, EUS-CDS with ECE-LAMS could be proposed in the first intent in case of distal malignant obstruction.