EUS-guided hepaticogastrostomy has been performed for many years with most published experience from outside the United States. The luminal access point can be from the esophagus, stomach, duodenum, or jejunum; biliary access can be either into the right or left intrahepatic system. Thus, we prefer the term EUS-guided transhepatic biliary drainage (ETBD). We describe what is believed to be the largest single-center U.S. experience of ETBD for management of benign and malignant biliary disease. This was a retrospective study of all ETBD conducted by 1 endoscopist between September 2014 and May2021. Two hundred fifteen patients underwent attempted ETBD: 85 for benign disease and 130 for malignant disease. Ninety-two patients (43%) had surgically altered anatomy (SAA). In 94 patients previously endoscopic attempts failed. The approach was transesophageal in 9, transgastric in 188, transduodenal in 5, and transjejunal in 5 patients. In 1 patient a bilateral approach was used. Standard fully covered self-expandable stents of 4- to 10-cm lengths and 8- or 10-mm diameters were used. Technical success was 95.3% and clinical success was 87.25%. Forty patients (18.6%) experienced adverse events (13 mild, 21 moderate, and 6 severe according to the modified American Society for Gastrointestinal Endoscopy lexicon). Mean follow-up was 257.31 ± 308.11 days for all patients (124.53 ± 229.86 days for benign disease and 457.27 ± 466.31 days for malignant disease). Seventy-four patients (34.4%) had died at the time of data collection (66 in the malignant cohort, 8 in the benign cohort). Of those with malignancy surviving >6 months, 17.4% required reintervention. ETBD is effective in the management of benign and malignant biliary obstruction for patients with SAA as well as native anatomy, with a modest adverse event rate.