OBJECTIVE: To determine the risk factors for and the incidence, morbidity, mortality, and outcome of pancreaticobiliary disease in patients who have had orthotopic heart transplantation. DESIGN: Retrospective case-control analysis. SETTING: University hospital-based heart transplantation center. PATIENTS: 20 case-patients with pancreaticobiliary disease and 40 controls; all patients received heart transplants between 1985 and 1994. Controls were matched to case-patients by time of transplantation and length of survival. MEASUREMENTS: Charts were reviewed and data were extracted using a structured data abstraction protocol. Risk factors assessed before transplantation were cause of heart disease, history of diabetes, reproductive history, and sex. Risk factors assessed at presentation of pancreaticobiliary disease were weight change after transplantation, alcohol use, use of medications, recent total parenteral nutrition, age at symptom onset, recent rejection episode, cyclosporine level, complete blood count, time between transplantation and onset of symptoms, body mass index, calcium level, liver function test results before and at symptom onset, and lipid profile. RESULTS: Pancreaticobiliary disease occurred in 20 of 255 transplant recipients (7.8%). The incidence of disease in these patients within 1 year after transplantation was 3.9% compared with an expected rate of 0.2% per year (P < 0.01). A decreased serum calcium level was the only risk factor found to differ significantly between the two groups (mean +/- SD, 2.19 +/- 0.17 mmol/L in case-patients and 2.31 +/- 0.14 mmol/L in controls; P = 0.005). The duration of hospitalization for the treatment of pancreaticobiliary disease was longer for patients who received transplants than for patients who did not receive transplants and were treated at Temple University Hospital during a similar period (17.1 days compared with 7.2 days; P < 0.001). However, the outcome was excellent in most patients. CONCLUSIONS: Pancreaticobiliary disease occurs 17.4 times (95% CI, 9.2 to 32.7 times) more frequently in patients receiving transplants than in the general population. It is a seldom recognized but apparently common complication of orthotopic heart transplantation that results in substantial morbidity and health care resource use. Further study is needed to ascertain why this condition occurs and how the risk for developing it can be reduced.