Acute cellular rejection (ACR) after orthotopic liver transplantation occurs in 50% to 80% of patients despite the recent advances in immunosuppressive therapy. Adjuvant use of ursodeoxycholic acid (UDCA) is theoretically attractive, but studies have shown conflicting results. In this randomized, controlled study, we evaluated the efficacy of UDCA in reduction of the incidence of ACR. Thirty patients were randomized to receive either UDCA (15 mg/kg) or placebo in addition to the standard triple-drug regimen; 14 patients received UDCA, and the rest received placebo, for 3 to 6 months. The diagnosis of ACR was based on histologic criteria. Three patients withdrew from the study within 1 month of therapy, all because of capsule size. There was no difference in the total incidence of ACR between the placebo and UDCA groups, with 12 and 11 episodes within 6 months, respectively; the overall incidence of rejection was 77%. There were also no differences in the incidence of recurrent rejection, in the number of rejection episodes occurring after 5 days of therapy, or in the use of OKT3. There was no difference in 1-year survival between groups. This study shows that adjuvant therapy with UDCA in addition to standard triple-drug immunosuppressive therapy does not reduce the incidence of ACR.