Although antibody to the hepatitis B surface antigen usually provides protection against hepatitis B virus (HBV) infection, recent reports indicate that this is not always the case. To study the possible role of immune responses to hepatitis B core antigen in immunity to HBV infection, chimpanzees were immunized with chimpanzee liver-derived or genetically cloned hepatitis B core antigen and later challenged with known infectious HBV. Two chimpanzees, which received liver-derived or cloned hepatitis B core antigen in Freund's adjuvant and developed hepatitis B core antibody and low-titer hepatitis B e antibody, were completely protected against HBV infection following challenge. In contrast, another chimpanzee, which received liver-derived hepatitis B core antigen without adjuvant, developed hepatitis B core antibody only in serum and had a subclinical HBV infection when challenged. These findings demonstrate that protection against HBV infection can be induced by immunization with hepatitis B core antigen in adjuvant and that protection, in this case, is not solely dependent on hepatitis B surface antibody. This fact has important implications in our understanding of the biology of HBV infection and in the design of future hepatitis B vaccines.