BACKGROUND & AIMS: Although hepatocellular carcinoma (HCC) occurs with increased frequency in patients with primary biliary cirrhosis (PBC), the exact frequency is relatively low. Optimal selection of PBC patients for HCC screening needs to be determined for effective screening. In this study, we aimed to explore clinical predictors of HCC in PBC patients. METHODS: We performed a case-control study using 17 PBC patients with HCC identified from 1976 to 2002 at the Mayo Clinic. Control PBC patients who had no evidence of HCC were selected for each case by matching the first year of their visit to the Mayo Clinic. All medical information was collected within 2 years from when the cases were diagnosed with HCC. Logistic regression models were used for the analyses. RESULTS: Age, sex, history of blood transfusion, current smoking, histologic stage at PBC diagnosis, any signs of portal hypertension, Mayo score, hemoglobin level, platelet count, aspartate aminotransferase level, and albumin level were associated with the presence of HCC (P < .05 for each). In multivariable analysis, older age (OR, 1.7; 95% confidence interval [CI], 1.1-2.5 for 5 years), male sex (OR, 9.7; 95% CI, 1.4-68.3), history of blood transfusion (OR, 5.0; 95% CI, 1.0-24.3), and any signs of portal hypertension (OR, 22.9; 95% CI, 3.4-155.3) were associated significantly with increased odds of HCC and yielded an excellent diagnostic performance (area under the receiver operating characteristics curve rate, 0.91). CONCLUSIONS: Older age, male sex, history of blood transfusion, and any signs of portal hypertension or cirrhosis indicate higher likelihood of HCC and should be considered for HCC screening. Further studies in larger patient cohorts are required to verify the diagnostic model.