Chimpanzees are susceptible to infection by di- No antibodies to the carboxyl terminus of HTLV-IUB gpl20 were observed in sera of chimpanzees inoculated with HTLV-ITIRF or with the brain-tissue strain, and those sera did not neutralize HTLV-IIIB. A rabbit immunized with the C-terminal portion of gpl20 acquired neutralizing antibodies that bound to four domains of the HTLV-UIB external envelope as analyzed by reactivity to 536 overlapping nonapeptides of gpl20. One of these domains in the variable region V3, with the amino acid sequence IRIQRGPGRAFVTIG (amino acids 307-321), bound to all chimpanzee sera that neutralized HTLV-IIIB but not to the serum of the HTLV-IUIRF-inoculated chimpanzee that did not neutralize HTLV-UIB. The HTLV-IIIRF sequence at the same location, ITKGPGRVIYA, was recognized by the serum of the HTLV-UIERF-inoculated chimpanzee but not by any sera of the HTLV-IUB-inoculated or LAV-i-inoculated chimpanzees. The HTLV-UIB residues RIQR and AFV and the HTLV-IIRF residues lysine and VIYA, flanking a highly conserved (3-turn (GPGR), appear to be critical for antibody binding and subsequent type-specific virus neutralization. This neutralization epitope, putatively consisting of a loop between two cysteine residues (amino acids 296 and 331) connected by a disulfide bond, is immunodominant in HIV-1-infected chimpanzees and induces antibodies restricted to the homologous viral strain.