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Understanding the earliest virological and immunological events in acute hepatitis C virus (HCV) infection may provide insight into the determinants of protective immunity. Four cases of HCV viremia with subsequent viral clearance, but without biochemical hepatitis or anti-HCV seroconversion, are reported from a prospective cohort study of prison inmates. Two of the subjects who developed sustained viremia were assessed for production of interferon (IFN)-γ, by use of the enzyme-linked immunospot (ELISPOT) method and by assessment of HCV cytotoxic T lymphocyte (CTL) activity, CD4 lymphocyte proliferative responses, HCV load, and genotype. After 2–6 months of viremia, all 4 subjects cleared serum HCV RNA. Specific cellular responses were detected in both of the subjects who were assessed, and production of IFN-γ was demonstrated in one subject. All subjects had weak, but consistent, serological …