We have previously documented that ursodeoxycholic acid exerts a beneficial effect on liver function and bile acid metabolism in patients with cystic fibrosis. We hypothesized that the mechanism of action may be related in part to the choleretic properties of the administered bile acid. We therefore compared hepatobiliary scintigraphic images obtained before and 1 yr after initiation of ursodeoxycholic acid therapy to document an improvement in bile flow in 13 patients with cystic fibrosis and hepatobiliary involvement. Before therapy, hepatobiliary scintigraphy documented biliary stasis with retention of the isotope in intrahepatic and extrahepatic bile ducts in nine patients; during therapy, duct dilatation decreased substantially in eight patients, with decreased intrahepatic retention and more rapid biliary outflow of the tracer. The time of appearance of isotope in the intestine decreased (from a mean of 36.9 ± 17.8 min to 18.8 ± 9.0 min; p < 0.01) in all patients in whom it had been abnormal, and the half-time of hepatic washout decreased from a mean of 35 ± 20.7 min to 26 ± 15.6 min (p < 0.05). During ursodeoxycholic acid administration enrichment of bile was achieved, with the mean ursodeoxycholic acid percent composition increasing from 5.8% ± 2.9% to 35.7% ± 8.5%. Ursodeoxycholic acid became the predominant bile acid in serum. Liver function improved in all 10 of the patients with abnormal values at baseline. We conclude that hepatobiliary scintigraphy is of value in monitoring the therapeutic responses of cystic fibrosis patients with liver disease to ursodeoxycholic acid therapy. These scintigraphic changes observed in our patients after treatment with ursodeoxycholic acid confirm the therapeutic effect of this bile acid in cystic fibrosis patients with associated liver disease. The effect may be mediated through an improvement in canalicular excretory function and biliary drainage. (Hepatology 1992;15:677–684).