The progression of fibrosis in hepatitis C virus (HCV) infection is a process in which genes interact with environmental factors. A "clotting process" is involved in fibrogenesis. ABO blood group distribution is associated with thrombotic disease, non-O blood group increasing the risk of venous thrombosis. The aim of the study was to investigate whether ABO blood type contributes to the severity of fibrosis. We studied blood group distribution in 346 French patients with HCV infection who underwent biopsies. The distribution of non-O blood group was 40%, 55%, 62%, 71%, and 73% for the F0, F1, F2, F3 and F4 fibrosis scores, respectively. Non-O blood group was associated with increased severity of fibrosis, even after adjustment on gender, age, duration of infection, and alcohol consumption (odds ratio 1.8, 95% confidence interval 1.0-2.9; P=.04). Non-O blood group is an independent risk factor for the progression of liver fibrosis in HCV infection.