A ntibodies against HIV-1 proteins in HIV-1-infected individuals share a cross-reactive idiotype defined by the monoclonal antiidiotypic antibody 1F7 (5). Using a computer algorithm based on the molecular recognition theory, regions of inverse hydropathy between the variable sequence of 1F7 and human monoclonal anti-HIV-1 antibodies were identified, which are assumed to be involved in idiotype-antiidiotype contacts. A peptide was designed from the proposed contact in the variable heavy chain framework 3-complementarity determining region 3 (FR3-CDR3) of human antibodies and was synthesized. This peptide is recognized by the antiidiotype 1F7 and inhibits the binding of 1F7 to human anti-HIV-1 antibodies which express the 1F7 idiotype. A survey of normal and HIV-1-infected sera revealed the presence of antibodies in infected sera which bind to the FR3-CDR3 peptide. The biological relevance of autoantibodies against a self idiotope associated with HIV-1 infection is discussed in the context of the regulation of the antibody response to HIV-1.