The monoclonal antibodies (MoAb) CR11-351 and KS1 are secreted by hybridomas generated with splenocytes from BALB/c mice immunized with the cultured human B lymphoid cells LG-2 (HLA-A2,A2,B27,B27). The 2 monoclonal antibodies immunoprecipitated components with a superimposable 2-dimensional gel electrophoretic profile from the cultured B lymphoid cells LG-2 and inhibited the cytotoxicity of the anti-HLA-A2,A28 T cell clone MI#3 to a similar extent. In crossinhibition experiments, the MoAb CR11-351 and KS1 completely inhibited the binding of each other to lymphoid cells with the appropriate HLA phenotype. Testing with a panel of HLA-typed lymphoid cells showed that the MoAb CR11-351 and KS1 display the same serologic specificity, since both of them react with HLA-A2 and/or A28 antigens bearing cells. The 2 monoclonal antibodies recognize distinct, although spatially close, determinants, since only the MoAb CR11-351 displays differential reactivity with HLA-A2 variant cell lines and reacts with HLA-A9 bearing B lymphoid cells. Analysis of MoAb CR11-351 and KS1 with syngeneic polyclonal and monoclonal antiidiotypic antibodies detected no sharing of idiotopes between the 2 monoclonal antibodies. In view of their reactivity with distinct determinants, these results are in agreement with the concept that the antigenic specificity of an antibody controls at least in part the expression of its idiotypes.