The spectrum of human immunodeficiency virus type 1 (HIV-1) isolates neutralized by antibodies from HIV-1-infected humans is broader than the spectrum of isolates neutralized by sera from animals immunized with purified gp120 subunits. This broader neutralization was due, in part, to the presence of antibodies to conserved gp120 conformational epitopes. Purified conformation-dependent gp120-specific human antibodies neutralized a wider range of virus isolates than human antibodies directed to linear determinants in gp120 and were also responsible for the majority of the gp120-specific CD4-blocking activity of HIV-1-infected human sera. A gp120 subunit vaccine that effectively presents these conformation-dependent neutralization epitopes should protect against a broader range of HIV-1 variants than a vaccine that presents exclusively linear determinants.