Whereas enhanced peripheral T-cell apoptosis and its association with autoimmunity have recently been reported, the apoptotic status of peripheral B cells in chronic hepatitis C virus (HCV) infection remains ambiguous. We therefore sought to investigate the sensitivity of peripheral B cells to apoptosis and to assess the possible benefits of antiviral treatment in mitigating these effects. Spontaneous apoptosis, the extent of apoptosis rescue, and NF-B expression in peripheral B cells were studied in patients with chronic HCV infections (group 1), in sustained responders after antiviral treatment (group 2), and in healthy controls (group 3). For group 1, spontaneous B-cell apoptosis was increased (26% ؎ 4.6%) and apoptosis rescue was altered (39%) compared to group 3 (18% ؎ 5% and 50%, respectively; P ؍ 0.001). In contrast, apoptosis and apoptosis rescue were similar for groups 2 and 3. Enhanced B-cell apoptosis was associated with decreased NF-B expression and was found only in CD5-negative (CD5 neg ) B cells, whereas CD5 pos cells were apoptosis resistant. Chronic HCV infection is associated with enhanced peripheral B-cell apoptosis and decreased apoptosis rescue. Successful antiviral treatment reverses these abnormalities to the levels seen in healthy individuals. The relative resistance of the CD5 pos B-cell subpopulation to apoptosis may play a role in HCV-related autoimmunity and lymphoproliferation.Hepatitis C virus (HCV) infection is considered to be the leading cause of chronic liver disease, with a prevalence rate of between 0.5 and 2% in Western countries and up to 10% in certain non-Western countries (12). The spontaneous resolution of chronic HCV infection is rare, suggesting that the virus actively evades the immune system and limits its ability to garner an effective response (2, 4). However, little is known about how this virus persists and whether its persistence is due to early innate or adaptive immune response alterations. It was recently and elegantly shown that the binding of the HCV envelope protein E2 to CD81 inhibits natural killer (NK) cell antiviral activity, allowing the persistence of HCV and the establishment of a chronic infection (5, 34). Although CD81 ligation by HCV E2 was demonstrated to costimulate T cells, members of our laboratory reported an enhanced level of peripheral T-cell apoptosis in chronic HCV infections and suggested that this increase could contribute to both viral persistence and disease severity (32). That study demonstrated a decreased expression of nuclear factor B (NF-B) in activated T cells of HCV-infected patients. Both enhanced apoptosis and decreased NF-B expression correlated with autoimmune markers such as circulating cryoglobulins and rheumatoid factor (RF). The pathogenetic link between HCV and B-cell lymphotropism in inducing both autoimmunity and lymphoproliferation is unclear The recent identification of the CD81 protein as one of the HCV receptor candidates on B lymphocytes (27) suggests a mechanism by which B cells are infected with or, alterna...