Background and Aims: EUS-guided biliary drainage is a technique being increasingly used when ERCP fails, and it has been the focus of multiple studies and investment in recent years. However, the proportion of cases for which it is really indicated has not been established. The aim of this study is to determine how often EUS-guided biliary drainage is needed in a tertiary-care level therapeutic endoscopy unit. Methods: This is a prospective cohort study at a single tertiary-care center with a high volume of therapeutic endoscopy. A thousand consecutive ERCPs performed from November 1, 2013 to September 12, 2014 were screened, and those with previous biliary intervention were excluded (n = 476). EUS-guided biliary drainage was performed in suitable patients with failed ERCP and malignant biliary obstruction. The main outcome measures were the rates of ERCP failure and EUS-guided biliary drainage. Results: A total of 524 native papilla ERCPs were performed (41.2% male; median age 60 years, range 6-97 years; 9.4% outside failed ERCP; 1.9% surgically altered anatomy). The ampulla was reached in 518 (98.9%) and not reached in 6 (1.1%) because of surgically altered anatomy (n = 2), malignant duodenal stenosis (n = 3), or both (n = 1). The overall ERCP failure rate was 1.7% (9/524). Cannulation was successful in 99.4% (515/518) and unsuccessful in 0.6% (3/518) of cases in which the ampulla was reached. EUS-guided biliary drainage was indicated in 0.6% (3/524) of all referred native papilla ERCPs, or 33% (3/9) of those patients with failed ERCP; EUS-biliary drainage was successful in all cases. Conclusions: In a tertiary-care center, use of advanced ERCP techniques results in a high technical success rate. EUS-guided biliary drainage was required in only 0.6% of native papilla ERCPs, and although a number of excellent indications exist, it should not replace good ERCP technique.