In renal transplant recipients, chronic hepatitis B virus (HBV) infection often leads to cirrhosis and liver failure. In this study, we investigated whether or not in these patients viral variants would emerge despite immunosuppression, and whether they are associated with a specific course of liver disease. In a population of 552 renal transplant recipients hepatitis B 24 surface antigen (HBsAg)-positive patients were available for a 2-year follow-up. By polymerase chain reaction (PCR) and DNA sequencing, HBV genomes with deletions in the middle of the core gene (C-gene) were found in 9 out of the 24 patients. Seven of the 9 patients (group I) showed either persistent or increasing amounts of these variants; all patients had cirrhosis, and 5 died of end-stage liver disease. The viral variants emerged at least 1 year before liver failure. In 2 out of the 9 patients, the core deletion variants disappeared, and no further deterioration of the liver function was observed thereafter. In the remaining 15 patients (group II) without deletion mutants detected at any time, only 3 had cirrhosis (P < .001, group I vs. II), and none died (P < .001). Between both groups, there were no statistically significant differences in the other relevant variables that were examined. These results indicate that HBV C-gene deletion mutants can accumulate in long-term immunosuppressed patients, and that their persistence is associated with progressive liver disease. The accumulation of these variants may be caused by the development of cirrhosis or could be involved in hepatopathogenesis.