An earlier study showed that approximately 5% of HIV-seropositive human sera contain gp120 antibodies that mimic CD4, seen as anti-idiotypic to the CD4 monoclonal T4.2. The present study shows the existence of a second type of CD4-mimicking gp120 antibody, which specifically binds to the CD4 monoclonal, OKT4A. This anti-idiotypic antibody to OKT4A is less frequent than the antibody reacting with T4.2. In two patients studied, this OKT4A binding antibody seems to appear as early during infection as the anti-idiotypic antibody to T4.2; however, the concentration varies more with time. In order to evaluate the possible clinical relevance of these CD4-mimicking antibodies, sera from 208 HIV-seropositive and 204 healthy seronegative individuals were screened. There was a significantly higher frequency of anti-idiotypic antibodies to T4.2 among HIV-positive individuals compared to healthy controls (p = 0.05). However, no correlation was found between the presence of CD4-mimicking antibodies and clinical classification of HIV-infected individuals.