The aim was to assess the specificity and functional significance of liver‐infiltrating and peripheral blood T cells in chronic hepatitis C. Peripheral blood mononuclear cells hepatitis C virus from 50 of 58 (86.2%) patients with chronic hepatitis C virus infection and 6 of 28 (21.4%) controls showed a proliferative T cell response to at least one of 16 synthetic peptides covering highly conserved regions of the core, envelope (El) and non‐structural regions (NS4) of hepatitis C virus. However, six immunodominant peptides were exclusively recognized by the proliferating blood mononuclear cells from 46 patients with chronic hepatitis C virus infection (79.3%). Fine specificity and HLA‐restriction were studied with 15 peptide‐specific CD4+ T cell lines and 23 T cell clones isolated from liver tissue and peripheral blood of 12 patients with chronic hepatitis C. It was demonstrated that the peptide‐specific response of CD4+ T cells was restricted to the presence of autologous accessory cells and HLA‐DR and ‐DP molecules. Eight peptide‐specific T cell lines and five T cell clones derived from liver tissue and peripheral blood, released interferon‐γ (200–6600 pg/ml) and tumor necrosis factor‐α (100–400 pg/ml) and no or little interleukin‐4 (<140 pg/ml) after peptide‐specific or mitogeneic stimulation, thus resembling a Th1‐like cytokine profile. Patients with active liver disease showed significantly higher proliferative responses to hepatitis C virus core peptides than asymptomatic hepatitis C virus carriers or complete responders to interferon therapy. In conclusion, class II‐restricted CD4+ T cell responses to some immunodominant epitopes within the hepatitis core region correlated with disease activity in chronic hepatitis C virus infection. Functionally, liver‐infiltrating and peripheral blood T cells released Th1‐like cytokines in response to the specific stimulus. Thus, it can be suggested that CD4+ T cells can mediate the pathogenesis of chronic hepatitis C virus induced liver disease.