BACKGROUND Endoscopic drainage of pseudocysts using the transpapillary and transmural approaches has been reported. We evaluated endoscopic drainage in 53 patients with symptomatic pancreatic pseudocysts in whom conservative management had failed. METHODS After preliminary endoscopic retrograde pancreatography, transpapillary drainage was attempted in 33 patients with pseudocysts that communicated with the main pancreatic duct. Transmural drainage of pseudocysts in contact with the stomach or duodenal wall was attempted in the remaining 20 patients and in 4 patients selected for combined transpapillary and transmural drainage. The cause of pseudocysts was chronic pancreatitis in 92%. The median pseudocyst size was 7.0 cm (range, 2 to 16). RESULTS Endoscopic drainage was technically successful in 50 patients (94%), of whom 47 had complete pseudocyst resolution. Complications occurred in 11% and included gallbladder puncture (n = 1) and bleeding (n = 2) after transmural drainage, and pancreatitis (n = 1) after transpapillary drainage; stent clogging resulted in abscess formation in 2 patients. Mean follow-up was 22 months (range, 1 to 70); pseudocysts recurred in 11 patients (23%), of whom 7 were successfully re-treated endoscopically. CONCLUSIONS Both transpapillary and transmural pseudocyst drainage are highly effective in patients with pseudocysts demonstrating suitable anatomy for these endoscopic techniques.