In a study of the immunologic significance of the genetic diversity present within single isolates of human immunodeficiency virus type 1 (HIV-1), the neutralization of viruses derived from molecular clones of the HIV-1 strain HTLV-IIIB by an extensive panel of sera was compared. Sera from HIV-1-infected patients and from goats immunized with polyacrylamide gel-purified HIV-1 envelope glycoprotein (gp120), native gp120, or gp120-derived recombinant peptides, showed marked heterogeneity in neutralizing activity against these closely related viruses. The change of a single amino acid residue in gp120 may account for such "clonal restriction" of neutralizing activity.