Background: Acute calculous cholecystitis is the obstruction of the cystic duct by a gallstone that leads to inflammation of the gallbladder necessitating cholecystectomy. Case Series: We present the cases of 2 patients with acute calculous cholecystitis who were deemed ineligible candidates for cholecystectomy because of their complicating medical histories. Both patients initially underwent cholecystostomy and drain placement with interventional radiology for management of acute calculous cholecystitis. Their large gallstones remained refractory to attempts at removal by electrohydraulic lithotripsy via the cholecystostomy access. The patients' gallstones were successfully removed via percutaneous ultrasonic lithotripsy during a collaborative procedure with interventional radiology and urology. Conclusion: An interdisciplinary approach using percutaneous cholecystolithotomy with rigid ultrasonic lithotripsy is an effective method for removing challenging gallstones in patients for whom traditional approaches fail.