Antisera to recombinant human immunodeficiency virus (HIV) proteins containing the entire envelope, gp160, or the central portion of the envelope, PB1, can inhibit fusion of virally infected cells in culture. This fusion inhibition is HIV-variant specific--that is, anti-gp160-IIIB inhibits fusion of isolate HTLV-IIIB-infected cells but not of isolate HTLV-IIIRF-infected cells. Both anti-gp160 and anti-PB1 are completely blocked in fusion inhibition activity by the addition of PB1 protein. A 24-amino acid peptide (RP135, amino acids 307-330) completely blocks fusion inhibition activity of both antisera and also blocks the activity of serum from a chimpanzee infected with HTLV-IIIB. Thus, the principal epitope that elicits fusion-inhibiting antibodies is located in the central portion of gp120.