The objective of this prospective cohort study was to describe the natural history of hepatitis C virus (HCV) infection and the effect of human immunodeficiency virus (HIV) on the clinical manifestations of HCV liver disease. Two hundred twenty-three hemophiliacs were followed in a comprehensive care setting with periodic clinical and laboratory evaluations. Dates of HIV seroconversion were determined retrospectively from frozen sera. HCV assays were performed by a "second generation" four-antigen recombinant immunoblot assay (RIBA 2). Liver failure was found after a latency period of 10 to 20 years in 9% of multitransfused HCV-positive/HIV-positive adult hemophiliacs without an AIDS-defining opportunistic infection or malignancy. Lymphocytopenia, decreased CD4 counts, and, possibly, thrombocytopenia were associated with liver failure which appeared to be accelerated by HIV disease and its treatment. This form of severe liver disease is being seen with increasing frequency among multi-transfused persons with hemophilia who are coinfected with HCV and HIV.