Background: Although the utility and safety of EUS and EUS-guided FNA is well known, there is a need for more data on outcomes and complications of EUS-guided drainage procedures. Objective: To evaluate the rates of technical success, treatment success, and complications of the graded dilation technique for performing EUS-guided drainage of peripancreatic fluid collections (PFCs) in a large cohort of patients. Also, the technical proficiency for performing EUS-guided drainage of PFCs was evaluated. Design: A prospective study of all patients undergoing EUS-guided drainage of PFC. Setting: A tertiary-referral center. Interventions: After passage of a 0.035-inch guidewire into the PFC by using a 19-gauge needle, graded dilation of the tract was sequentially performed by using a 4.5F ERCP cannula, a 10F ERCP inner guiding catheter, and an 8-mm balloon dilator. A transmural stent and/or drainage catheter was then deployed. Main Outcome Measurements: To evaluate the technical success, treatment success, and complications of the graded dilation technique. Technical proficiency was evaluated by comparing the procedural duration between the first 25 cases (group A), with a later cohort of patients (group B, n = 29) who underwent EUS-guided drainage of a single PFC. Results: Sixty patients (41 men; mean age 51 years [range 20-79 years], 6 multiple PFCs) underwent EUS-guided drainage of a PFC (types included 36 pseudocyst, 15 abscess, and 9 necrosis) over a 42-month period. The rates of technical and treatment success were 95% and 93%, respectively. A minor complication of stent migration was encountered in 1 of 60 patients (1.7%). There was no significant difference in patient or clinical characteristics between group A and B patients who were undergoing drainage of a single PFC. Although there was no significant difference in technical or treatment outcome, median procedural duration was significantly shorter for group B than for group A patients (25 vs 70 minutes; P < .001). Procedural duration for performing EUS-guided drainage of a single PFC was more likely to be <30 minutes in group B than in group A patients (crude odds ratio [OR] 18.8; P < .001), which remained significant (adjusted OR 11.8; P = .01), even after adjusting for patient age; serum albumin; type, location, and size of PFCs; drainage modality (stent vs stent plus drainage catheter); and site of endoscopic access for establishing drainage. Conclusions: In this study, EUS-guided drainage of a PFC could be performed safely by using the graded dilation technique, with a successful outcome in a majority of patients. Technical proficiency, with regard to procedural duration, improved significantly after the first 25 cases. © 2008 American Society for Gastrointestinal Endoscopy.