Background: Although EUS-guided cyst-gastrostomy is increasingly being performed, there are no studies that compare the clinical outcomes and cost-effectiveness with surgical cyst-gastrostomy. Objectives: To compare the clinical outcomes of EUS-guided cyst-gastrostomy with surgical cyst-gastrostomy for the management of patients with uncomplicated pancreatic pseudocysts and to perform a cost analysis of each treatment modality. Design: A retrospective case-controlled study. Setting: A tertiary-referral center. Patients: Consecutive patients with uncomplicated pancreatic pseudocysts managed by surgical and EUS-guided cyst-gastrostomy. Methods: An independent observer blinded to all clinic outcomes matched each patient who underwent a surgical cyst-gastrostomy with 2 patients who underwent an EUS-guided cyst-gastrostomy for age, etiology of pancreatitis, and the size of the pseudocyst. Main Outcome Measurements: Rates of treatment success, complications, and reinterventions; length of postprocedure hospital stay; and cost associated with each treatment modality. Results: Ten patients (6 men; mean age 42.3 years, range 22-65 years) who underwent surgical cyst-gastrostomy were matched with 20 patients who underwent an EUS-guided cyst-gastrostomy. There were no significant differences in demographics, major comorbidities, and clinical characteristics between both cohorts. Although there were no significant differences in rates of treatment success (100% vs 95%, P = .36), procedural complications (none in either cohort), or reinterventions (10% vs 0%, P = .13) between surgery versus an EUS-guided cyst-gastrostomy, the mean length of a postprocedure hospital stay for an EUS-guided cyst-gastrostomy was significantly shorter than for surgical cyst-gastrostomy (2.65 vs 6.5 days, P = .008). The average direct cost per case for EUS-guided cyst-gastrostomy was significantly less when compared with surgical cyst-gastrostomy ($9077 vs $14,815, P = .01), which corresponded to a cost savings of $5738 per patient. Limitations: Retrospective, nonrandomized design; patients with pancreatic abscess or necrosis were not evaluated; a limited sample size and a short duration of follow-up. Conclusions: EUS-guided cyst-gastrostomy should be considered as a first-line treatment approach for patients with uncomplicated pancreatic pseudocysts, because the procedure is cost saving and is associated with a shorter length of a postprocedure hospital stay when compared with surgical cyst-gastrostomy. There was no significant difference in clinical outcomes between both treatment modalities. © 2008 American Society for Gastrointestinal Endoscopy.