The so-called cosmopolitan strains of human T cell leukemia/lymphotropic virus type I (HTLV-I) from Japan, Africa, the West Indies, and the Americas differ only slightly (<3%) in their genomic sequence. On the other hand, the Melanesian strains of HTLV-I are somewhat more divergent, exhibiting only 93% sequence similarity with the cosmopolitan strains. Despite this difference, sera from individuals infected with Melanesian strains cross-react with T cells infected with cosmopolitan strains of HTLV-I, indicating an overall conservation of the B cell immunoprevalent epitopes. Neutralizing antibodies against HTLV-I in sera from virus-infected Africans and Melanesians were assayed by determining their ability to block the formation of syncytia in cocultures of 8166 and T cell lines harboring either, cosmopolitan or Melanesian HTLV-I isolates. All six African sera blocked the formation of syncytia with cells infected with HTLV-I-C91-PL, a viral isolate from the United States. Similarly, ail six Melanesian sera inhibited syncytium formation with cells infected with HTLV-I-MEL3, a virus isolate from the Solomon Islands. Although most of these sera inhibited syncytium formation in cell cultures carrying the cosmopolitan as well as the Melanesian HTLV-I strains, neutralizing antibody titers tended to be higher against the homologous virus. All sera failed to inhibit syncytium formation when cells were infected with HTLV-II. These data indicate the involvement of one or more epitopes in syncytial formation, some of which are conserved in all strains of HTLV-I. If antigenic determinants for neutralization play an important role in protection against HTLV-I infection, as suggested by studies in infected rabbits and humans, vaccines for worldwide application should include the envelope proteins from a Melanesian strain of HTLV-I.