BACKGROUND: It is unclear whether mild to moderate iron overload in liver diseases other than hereditary haemochromatosis (HH) contributes to hepatocellular carcinoma. This study examined the association between hepatic iron grade and hepatocellular carcinoma in patients with end-stage liver disease of diverse aetiologies. METHODS: The prevalence of hepatic iron overload and hepatocellular carcinoma was examined in 5224 patients undergoing liver transplantation. Explant pathology reports were reviewed for the underlying pathological diagnosis, presence of hepatocellular carcinoma and degree of iron staining. The distribution of categorical variables was studied using chi(2) tests. RESULTS: Both iron overload and hepatocellular carcinoma were the least common with biliary cirrhosis (1.8 and 2.8% respectively). Hepatocellular carcinoma was the most common in patients with hepatitis B (16.7%), followed by those with hepatitis C (15.1%) and HH (14.9%). In the overall cohort, any iron overload was significantly associated with hepatocellular carcinoma (P=0.001), even after adjustment for the underlying aetiology of liver disease. The association between hepatic iron content and hepatocellular carcinoma was the strongest in patients with biliary cirrhosis (P<0.001) and hepatitis C (P<0.001). CONCLUSIONS: Iron overload is associated with hepatocellular carcinoma in patients with end-stage liver disease, suggesting a possible carcinogenic or cocarcinogenic role for iron in chronic liver disease.