Western blot analysis of 16 serum specimens from Seminole Indians demonstrated that 14 reacted with the type-specific recombinant epitope (rgp46II+) of human T lymphotropic virus type II (HTLV-II), whereas the remaining 2 specimens did not (rgp46II-). Both rgp46II- specimens demonstrated presence of HTLV-II genome by polymerase chain reaction analysis. Culture of 1 of these specimens demonstrated presence of type C retrovirus particles by electron microscopy, and p24gag antigens were detectable in culture supernatant. Nucleotide sequence analysis of 557 bp in the env gene (position 5405-5961) from 2 each of the rgp46II- and rgp46II+ specimens demonstrated sequence conservation in the rgp46II epitope (K-55(162-205)). Thus, lack of immune reactivity to rgp46 is not due to sequence variation within this epitope. This observation suggests that immunodominant env epitopes may not be universally recognized. Therefore, specimens with p24gag and r21eenv reactivity in modified Western blot assays should be further tested by more sensitive techniques.