Background: Various methods to drain pancreatic pseudocysts by using EUS guidance have been reported in the literature. Objective: A new drainage technique is described that uses a modified needle knife advanced over a guidewire positioned in the pseudocyst by EUS guidance. Design: Retrospective chart review. Setting: Academic medical center. Patients: Consecutive subjects from December 1, 2002, to January 10, 2005, with symptomatic pseudocysts in whom EUS-guided drainage was attempted. Interventions: By using a therapeutic linear echoendoscope, a 19-gauge aspiration needle was inserted into the pseudocyst. A guidewire was placed through the needle, and a needle knife with the cutting wire protruding and bent was advanced over the guidewire to contact the stomach mucosa. The needle knife was then advanced by using electrocautery into the pseudocyst. The cystenterostomy was dilated by using a balloon over the guidewire. One to 4 stents were placed through the tract. Main Outcome Measurements: Successful pseudocyst drainage. Results: A total of 21 of 23 patients underwent technically successful pseudocyst drainage. One patient had self-limited hypotension during the procedure. Another patient had free intraperitoneal air after the procedure but correct stent placement. Limitations: Retrospective analysis, small sample size. Conclusions: In this preliminary experience, wire-guided pseudocyst drainage with a modified needle knife appears effective and safe while allowing for a more controlled pseudocyst puncture.