Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) is an alternative to surgery for acute cholecystitis (AC) in poor operative candidates. However, the role of EUS-GBD in non-cholecystitis (NC) indications has not been well studied. We compared clinical outcomes of EUS-GBD for AC and NC indications. Consecutive patients undergoing EUS-GBD for all indications at a single center were retrospectively analyzed. Fifty-one patients underwent EUS-GBD during the study period. Thirty-nine (76%) patients had AC while 12 (24%) had NC indications. NC indications included malignant biliary obstruction (n = 8), symptomatic cholelithiasis (n = 1), gallstone pancreatitis (n = 1), choledocholithiasis (n = 1), and Mirizzi’s syndrome (n = 1). Technical success was noted in 92% (36/39) for AC and 92% (11/12) for NC (p > 0.99). Clinical success rate was 94% and 100%, respectively (p > 0.99). There were 4 adverse events in the AC group and 3 in the NC group (p = 0.62). Procedure duration (median 43 vs 45 minutes, p = 0.37), post-procedure length of stay (median 3 vs 3 days, p = 0.97), and total gallbladder related procedures (median 2 vs 2, p = 0.59) were similar. EUS-GBD for NC indications is similarly safe and effective as EUS-GBD in AC.