Hepatitis B virus (HBV)-associated nucleocapsid antigen (HB core and HB e) is believed to be a major target for T cell-mediated hepatocellular damage in chronic HBV carriers. Studies were undertaken to determine whether both nucleocapsid Ag could be recognized by T cell lines from peripheral blood mononuclear cells (PBMC) from patients with chronic hepatitis B. After cultivation in the presence of rHBcAg or purified HBeAg, growing cells were cloned by limiting dilution in the presence of PHA, IL-2 and allogenic feeder cells. Four HBcAg-reactive and three HBeAg-reactive T cell lines from two patients were generated by proliferation assays. None of the cell lines responded to HB surface Ag or PPD. Four lines were of the CD8+ CD11b- cytotoxic phenotype, two of the CD4+ Leu8- helper phenotype, and the remaining one consisted of mixed populations of CD4+ Leu8+ and CD4+ Leu8- cells. Cross-reactivity study showed that a HBcAg-induced CD4+ T cell line responded to HBeAg, and similarly a HBeAg-induced CD8+ T cell line responded to HBcAg. The reactions were inhibited by HLA class II antibody, but not by class I Ab.