A body of evidence has Suggested a close link between chronic hepatitis C virus (HCV) infection and B cell abnomalities, including mixed cryoglobulinemia, rheumatoid factor (RF) production, and lymphoproliferative disorders that may develop into non-Hodgkin's lymphoma. Recent studies have demonstrated the expansion of CD5(+) B cells in the peripheral blood of chronic hepatitis C patients (CHC). As CD5(+) B cells, which are capable of producing autoantibodies and RE, are apparently crucial for the development of HCV-associated pathogenesis, the fate of both the CD5(+) and CD5(-) B cell subsets upon chronic HCV infection is of interest. In this study, the degree to which chronic HCV infection induces apoptosis in each B cell subset was investigated. Our results demonstrated that peripheral CD5(-) B cells were more susceptible to apoptosis than CD5(+) B cells in CHC. Furthermore, plasma levels of IL-4, IL-10, and IL-12 were significantly elevated in CHC, thus suggesting that these interleukins protect CD5(+) B cells from apoptosis. The rationale for the differential susceptibility of distinct B cell subsets in CHC is also discussed with regard to extrahepatic manifestations associated with chronic HCV infection. (C) 2009 Elsevier Inc. All rights reserved.