The capacity of the nucleocapsid protein of HBV to function as a T-cell independent antigen in man was studied. When T-cell depleted B-cell cultures were challenged with E coli-derived HBcAg, anti-HBc production was registered in culture supernatants from the majority of chronic HBsAg carriers in a quiescent stage of disease. In contrast, similarly prepared and stimulated cultures from donors with natural acquired immunity to hepatitis B or HB-susceptible controls were non-responsive. Addition of autologous T-cells effectively restored anti-HBc responsiveness in T-cell depleted B-cell cultures from HB-immune donors, demonstrating the T-cell dependency for anti-HBc induction in natural HBV-infection.