Human immunodeficiency virus (HIV)-l-infected rapid and slow progressors showed differential humoral responses against HIV envelope peptides and proteins early in infection. Sera from slow progressors reacted more strongly with short envelope peptides modeling gp160NL4-3, predominantly in gp41. Reactivity to six peptides (in constant regions C3, C4, and C5 of gp120 and in gp41) correlated with slower progression. In a novel association, reactivity to three peptides (in constant regions C1 and C3 and variable region V3 of gp120) correlated with faster progression. Envelope peptide reactivity correlated with subsequent course of disease progression as strongly as did reactivity to gag p24. Patients heterozygous for 32-bp deletions in the CCR5 coreceptor reacted more frequently to an epitope in gp41. Rapid progressors had greater gp120 native-to-denatured binding ratios than did slow progressors. While antibody-dependent cellular cytotoxicity against gp120 did not strongly differentiate the groups, slow progressors showed a broader neutralization pattern against 5 primary virus isolates.