Background: Chronic antigen exposure and/or ageing increases the frequency of T-box expressed in T cells (T-bet)-expressing B-lymphocytes in mice. The frequency and significance of B-cell T-bet expression during chronic hepatitis C (HCV) infection in human subjects has never been described. Methods: Healthy controls, cirrhotic and noncirrhotic HCV-infected patients, and non-HCV patients with cirrhosis were recruited. Peripheral blood mononuclear cells were phenotyped for expression of T-bet and related markers by flow cytometry. In a subset of patients who underwent antiviral therapy and were cured of HCV infection (sustained virological response), the dynamics of T-bet expression in B cells was monitored. After cure, convalescent B cells were tested for T-bet expression after re-exposure to infected plasma or recombinant HCV proteins. Results: Forty-nine patients including 11 healthy donors, 30 hepatitis C-infected individuals (nine with liver cancer, 13 with cirrhosis, eight without cirrhosis) and eight patients with cirrhosis due to non-HCV-related cause were recruited. We found that B cells in patients with chronic HCV exhibited increased frequency of T-bet+ B cells relative to noninfected individuals (median 11.5% v. 2.2%, P<.0001) but that there were no significant differences between noncirrhotic, cirrhotic and cancer-bearing infected individuals. T-Bet(+) B cells expressed higher levels of CD95, CXCR3, CD11c, CD267 and FcRL5 compared to T-bet(-) B cells and predominantly exhibit a tissue-like memory CD27(-)CD21(-) phenotype independent of HCV infection. T-bet(+) B cells in HCV-infected patients were more frequently class-switched IgD(-)IgG(+) (40.4% vs. 26.4%, P=.012). Resolution of HCV infection with direct-acting antiviral (DAA) therapy leads to a marked reduction in the frequency of T-bet(+) B cells (median 14.1% pretreatment v. 6.7% end of treatment v. 6.1% SVR12, P.01). Re-exposure of convalescent (cured) B cells to viremic plasma and recombinant HCV E2 protein led to re-expression of T-bet. Conclusion: Chronic antigenemia in chronic HCV infection induces and maintains an antigen-specific T-bet(+) B cell. These B cells share markers with tissue-like memory B cells. Antigen-driven T-bet expression may be a critical suppressor of B-cell activation in chronic HCV infection.