Aiming to develop an animal model for anti-CD4 autoimmunity reflective of that observed in HIV-1 patients, we injected the selected peptides p1, p28 and p29 as the major immunogenic epitopes into HLA-DR4 and human CD4 transgenic DBA/16J mice, as well as into C57BL/6 and DBA mice. We document a decrease of CD4+ cells in peripheral blood and spleen after immunization with the human CD4-p28 immunogenic peptide of transgenic mice expressing human CD4, human HLA class II and mouse class II I-A(q) (HLA-DR4-huCD4-I-A(q+)); however, no decrease of CD4 cells was found in transgenic HLA-DR4-huCD4-I-A(q-) mice or in control C57BL/6 and DBA immunized mice. Overall, the consistency of CD4 reduction and immunological recognition of p28 peptide favors the HLA-DR4-huCD4-I-A(q+) mouse as the most promising autoimmune mouse model.