The difficulty in managing complex biliary tract calculi is exemplified in patients with primary intrahepatic calculi. Standard surgical and endoscopic approaches often fail to clear calculi in these patients who have recurrent episodes of cholangitis. The success of the holmium laser for urologic calculi led us to adapt treatment strategies for primary and secondary biliary tract calculi where standard treatments had been unsuccessful. Our goals were to remove all calculi, prevent recurrent sepsis, and preserve hepatic parenchyma. Thirty-six patients with complex biliary calculi were treated. After sepsis was controlled and the extent of calculi was evaluated, appropriate access to and drainage of the biliary tract was achieved. Holmium laser lithotripsy was performed under video guidance using flexible choledochoscopes and a 200 micro laser fiber generating 0.6 to 1.0 joules at frequencies of 6 to 10 Hz. Lithotripsy procedures were repeated until cholangiography and cholangioscopy confirmed the clearance of calculi. Twenty-two patients of Asian descent with primary intrahepatic calculi and 14 patients with secondary intrahepatic calculi were treated. Access to the biliary tract could be accomplished through percutaneous catheter tracts, T-tube tracts, or the cystic duct during laparoscopic cholecystectomy. Biliary drainage was by biliary enteric anastomosis or endoscopic sphincterotomy. Complete stone clearance required an average of 3.9 procedures (range 1 to 15) for patients with primary intrahepatic calculi and 2.6 procedures (range 1 to 10) for patients with secondary intrahepatic calculi regardless of stone composition. No patient required hepatic resection and no complications or deaths were attributed to the holmium laser. Clearance of calculi can reliably and safely be achieved with a holmium laser regardless of stone composition or location while preserving hepatic parenchyma and preventing recurrent sepsis.