The presence of antibodies reactive to a recently cloned host-derived antigen GOR is highly correlated with the presence of antibodies to the hepatitis C virus (HCV). We explored the molecular basis for this observation, and address the following question: are antibodies reactive with GOR19-27 (QKAKSNPNR) a result of a cross-reactivity triggered by the antigenic region at residues 9-17 of HCV core (RKTKRNTNR)? We compared the relative antibody avidity between antibodies reactive to both regions, and determined the residues essential for antibody binding using substitution peptide analogues. Of 96 sera assayed, 60 were found positive for anti-HCV, and of these 55 were found to react with HCV core. Twenty-nine sera were found reactive to the GOR peptide, and these were all reactive to HCV core. In most cases the relative antibody avidity of antibodies reactive to GOR was higher for the HCV core peptide. In 21 of the GOR-reactive sera we were able to determine the essential residues for antibody binding. The essential residues in > 50% of all tested sera coincided with the well conserved residues Lys10, Lys12, Asn14, and Asn16. Also, reactivity to GOR was not related to any certain serotype of antibodies to HCV. Taken together, these findings explain at the molecular level the observed cross-reactivity between these two proteins, since sequence homology per se is not evidence for cross-reactivity.