BACKGROUND: One of the problems in prosthetic-valve recipients is the development of gallstones. We suggested that the use of a heart-lung machine may be closely related to gallstone formation. The objective of this study was to clarify the efficacy of ursodeoxycholic acid (UDCA) in the prevention of gallstone formation after open cardiac surgery. METHODS: One hundred and six patients without gallstones who underwent cardiac surgery in which a heart-lung machine was used were randomly divided into two groups: group A, comprising 54 patients who did not receive UDCA, and group B, comprising 52 patients who received UDCA (600 mg daily for 6 months from 1 week before surgery). Both groups were followed by ultrasonography for 60 months. Blood markers of hemolysis (hemoglobin, reticulocyte count, haptoglobin, total bilirubin, and lactate dehydrogenase) were evaluated before, immediately after, and at 3 weeks and 3, 6, 12, 24, and 60 months after surgery. RESULTS: In groups A and B, cumulative incidence rates for gallstone formation were 15.1% and 0% at 3 months, 23.0% and 0% at 6 months, 29.2% and 2.0% at 12 months, 29.2% and 8.4% at 24 months, and 29.2% and 8.4% at 60 months, respectively. In regard to the composition of the gallstones, they were considered to be mainly black pigment stones. CONCLUSIONS: The prophylactic administration of UDCA resulted in a significant decrease in the incidence of gallstones after open cardiac surgery.