In this study we have determined the incidence of hepatocellular carcinoma (HCC) development in primary biliary cirrhosis (PBC) and its effects on patient survival. Six hundred and sixty seven patients with liver histology compatible with or diagnostic of PBC were seen over a 20-year period. Two hundred and seventy three patients who had stage III or IV disease on their last biopsy and who had been followed up for at least 1 year following that biopsy (total follow-up with advanced disease 2,010 patient years) were identified (243 female, 30 male). Patients who developed HCC were identified and their confounding risk factors were excluded. Mayo risk scores were calculated for each clinic attendance and expected survival for each time point was compared with subsequent actual survival. Sixteen cases of HCC were seen in the patients with stage III or IV disease on last biopsy, providing an overall incidence of 5.9% in this group. Fourteen of these patients had died of HCC related causes, and 2 patients were alive at the census point. The incidence of HCC was significantly higher in males with stage III/IV disease than in females (20% vs. 4.1%, P < .005). Nine of one hundred and eight (8.3%) total female deaths in this group was attributable to HCC compared with 5 of 11 (45.5%, P < .05) male deaths. HCC was not seen in any of the 394 patients with stage I and II PBC followed-up over the same time period. Throughout the disease course of all PBC patients with HCC, the Mayo prognostic model over-predicted survival. Whereas it is a relatively rare complication of cirrhotic PBC in women, HCC is a relatively common cause of death in male PBC patients with cirrhosis. HCC typically develops several years after the onset of cirrhosis, and is poorly predicted by prognostic models. In view of these findings, consideration should be given to careful screening for HCC in male PBC patients with cirrhosis. The risk of HCC development may be an additional reason to consider earlier transplantation in these patients.