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)- gamma, 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- gamma was demonstrated in one subject. All subjects had weak, but consistent, serological reactivity against HCV nonstructural proteins on immunoblot testing, despite repeatedly nonreactive HCV ELISA tests. These cases highlight the potential for cellular immune responses against HCV to facilitate viral clearance, responses that may model those required for effective HCV vaccination.