We have observed that certain antisera to HLA antigens suppress the in vitro proliferation of lymphoblastoid cell lines. An antiserum to HLA-B8 demonstrated suppressor activity associated with the presence of B8 antigen on the target LCLs; this activity was removed by absorption with platelets or with B8-positive LCLs. An antiserum to HLA-DRw7 suppressed proliferation of all six DRw7-positive LCLs and none of 12 DRw7-negative LCLs; this activity was removed by absorptions with three DRw7-positive LCLs, each representing a different HLA-D allele (i.e. Dw7, 10 and 11); it could not be removed by triple serial absorptions with platelets from multiple-donor pools. These experiments indicate that the suppressor activity of this serum is specifically associated with antibodies to DRw7. Our model of LCL growth suppression by HLA antisera is easily manipulated and provides a definitive tool for further characterizing HLA antigens and antisera in a complement-independent system.