We previously described a cytoplasmic antigen, detected by monoclonal antibodies, in hepatocytes of chimpanzees experimentally infected with the parenterally transmitted form of non-A, non-B hepatitis virus or with the hepatitis delta virus. The expression of this antigen appears to be a host-specified response to infection with these two hepatitis viruses but not with hepatitis A virus, hepatitis B virus or enterically transmitted non-A, non-B hepatitis virus. To determine whether this antigen, found in parallel with the hepatocyte cytoplasmic structures described previously, is associated with interferon, as suggested by others, we studied by immunofluorescence liver biopsies from chimpanzees treated with an interferon inducer or exogenous interferon for the presence of the antigen. In two hepatitis B virus carrier chimpanzees and one normal chimpanzee treated with the interferon inducer polyinosinic-poly-ribocytidylic acid-poly-l-lysine carboxymethylcellulose, the antigen became detectable in hepatocytes within 2 weeks of initiation of the treatment, remained detectable throughout the treatment and disappeared within 4 weeks after treatment was terminated. Electron microscopy revealed that the biopsies positive for the antigen exhibited the hepatocyte cytoplasmic changes; convoluted membranes and microtubular aggregates, identical to those described originally for chimpanzees infected with non-A, non-B hepatitis virus. The antigen was not detected in any of the biopsies from a control chimpanzee that received only the carboxymethylcellulose used to stabilize the interferon inducer. In addition, liver biopsies obtained from a hepatitis B virus carrier chimpanzee during treatment with exogenous human leukocyte interferon were found to be positive for the antigen as well. It is likely that expression of this antigen and induction of the hepatocyte cytoplasmic structures are a host response to interferon induced by non-A, non-B hepatitis virus and hepatitis delta virus infections.