Background/Aims: T- lymphocyte reactivity against viral antigens may represent the only immunological marker of host contact with a virus. Aim of the present study was to investigate whether vertical exposure to hepatitis C virus (HCV) could activate HCV- specific T- cell responses that may represent a biomarker of previous contact with the virus, and possibly contribute to the low rate of vertical HCV transmission. Methods: We studied 28 children born from chronically HCV- infected mothers. HCV- specific activation and proliferation of CD4+ lymphocytes and cytokine production were evaluated in cultures of peripheral blood mononuclear cells (PBMCs) stimulated in vitro with HCV- peptides. Results: HCV- specific CD4+ cell reactivity was observed in 20 out of the 28 children (71% ). The proliferation of HCV- specific CD4+ cells was more frequent and vigorous in children than in their mothers. In children, but not in the mothers, activation of CD4+ cells upon stimulation with HCV- peptides was directly correlated with proliferation. Early upon stimulation with HCV- peptides, lymphocytes from children produced lower levels of IL- 10 than lymphocytes from the mothers. Conclusions: Vertical exposure to HCV induces the development of viral- specific CD4+ cell- mediated immune responses, possibly endowed with protective function against infection, which may contribute to the low rate of vertical HCV transmission. Background / Aims: T-lymphocyte reactivity against viral antigens may represent the only immunological marker of host contact with a virus. Aim of the present study was to investigate whether vertical exposure to hepatitis C virus (HCV) could activate HCV-specific T-cells responses that may represent a biomarker of previous contact with the virus, and possibly contribute to the low rate of vertical HCV transmission. Methods: We studied 28 children born from chronically HCV- infected mothers. HCV-specific activation and proliferation of CD4 + lymphocytes and cytokine production was evaluated in cultures of peripheral blood mononuclear cells (PBMCs) stimulated in vitro with HCV-peptides. Results: HCV-specific CD4 + cell reactivity was observed in 20 out of the 28 children (71%). The proliferation of HCV- specific CD4 + cells was more frequent and vigorous in children than in their mothers. In children, but not in the mothers, activation of CD4 + cells upon stimulation with HCV- peptides was directly correlated with proliferation. Early upon stimulation with HCV-peptides, lymphocytes from children produced lower levels of IL-10 than lymphocytes from the mothers. Conclusions: Vertical exposure to HCV induces the development of viral- specific CD4 + cell- mediated immune responses, possibly endowed with protective function against infection, which may contribute to the low rate of vertical HCV transmission.