Updated information on liver disease in transfusion-dependent beta-thalassemia is lacking. We conducted a multicenter study within the Cooleycare Group to describe the clinical and histopathological features of liver disease in currently treated thalassemics. Two-hundred and three thalassemics with laboratory signs of liver disease were eligible. Liver biopsy was performed in the 129 (63.5%) who consented (age 26+/-7 years). Biological samples were sent to the central laboratory. Anti-hepatitis C virus (HCV) antibodies were found in 118 patients (91%), 85 (72%) of whom were viremic. Ninety-one patients (70%) had abnormal aminotransferase concentrations. In the 117 liver biopsies that met the criteria for evaluation (88%), the median Ishak's necroinflammatory and fibrosis scores were 4 (range, 0-9) and 2 (range, 0-6), respectively. Significant fibrosis (score> or= 3) was found in 53 (45%); 9 (8%) had cirrhosis. At multivariate analysis, necroinflammation was related to HCV viremia, and fibrosis to increased serum aminotransferases, higher iron stores (including serum ferritin, Deugnier's total iron score, and liver iron content) and male gender (p< 0.05). In HCV-RNA negative subjects, the median total iron score was 27 (range, 0-52). Iron accumulated in both mesenchymal cells and hepatocytes, and the presence of a lobular gradient was interpreted to indicate intestinal hyperabsorption. Transfusion-dependent thalassemics have mild liver necroinflammation, mainly attributable to HCV infection. Significant fibrosis is frequent, and its progression is mostly influenced by iron overload which, with current therapy regimens, may be attributable to both erythrocyte catabolism and iron hyperabsorption.