The hypothesis that increasing chronicity of cholelithiasis is associated with a progressive alteration of the enterohepatic circulation, resulting in a decrease in bile salt pool size and reversion of hepatic bile composition to a less lithogenic state, was tested in the prairie dog gallstone model. During the early phases of cholesterol cholelithiasis, both hepatic and gallbladder bile were saturated with cholesterol, and the bile salt pool size was normal. As stones became more chronic, the gallbladder was increasingly removed from the enterohepatic circulation, bile salt recycling increased and the pool size decreased. Despite this decrease in pool size and persistence of lithogenic gallbladder bile, hepatic bile composition reverted to a less lithogenic state. These data suggest that the sequelae of functional cholecystectomy are analogous to those of cholecystectomy, In addition, it appears that the liver and gallbladder interact in a dynamic manner, continually influencing the function of each other.