Antibody response to conserved human immunodeficiency virus type 1 (HIV-1)mB gp160 epitopes was longitudinally examined in HIV-1-infected persons. Twelve hundred individuals were evaluated, and sequential sera from 25 rapidly progressing (RP) and 30 nonprogressing (NP) subjects collected over an average of 4 years were examined. Initial sera from the RP group contained greater reactivity to a gpl20 epitope defined by peptide 503–528 than did sera from the NP group (P <.00 1). Reactivity declined with sequential sera for the RP group, paralleling disease progression. Conversely, antibody recognition to this site developed in 23% of the NP group with time. However, 60% of the NP group never developed a response to this epitope. This suggests sequential examination of antibody response to an epitope within the gp120 carboxylterminus may have prognostic significance. No association between antibodies directed against the gp160 epitopes and in vitro neutralizing activity against HIV-1mB was observed.