The nature of the antigens recognized by mixed lymphocyte response-generated suppressor cells is currently unknown. Previous investigations have yielded conflicting results, with different studies finding that suppressor cells recognize HLA class I antigens, class II antigens, or neither. To characterize the antigens recognized by suppressor cells (modulators) further, we generated 36 different modulators and assayed them for suppressor activity against a random 48-member HLA-typed panel in a total of 473 assays. Logistic regression analysis of the data revealed that suppression was correlated with B and DQ antigenic sharing between the original stimulator (used to generate the suppressor cells) and the test culture stimulator (p = 0.0043 and 0.0277, respectively). A role for DR antigen sharing could not be excluded. Overall, 35% of all suppressed assays could not be accounted for by the sharing of either any classical private HLA antigens, or of HLA-A or B locus cross-reactive group specificities. Suppression in these instances may involve the sharing of minor antigenic determinants, unidentified private HLA epitopes, or possibly another gene related to suppression that exists in linkage disequilibrium with the HLA-B locus or the DQ subregion.