Individuals of known HLA phenotype were used to examine the specificity of secondary proliferative (restimulation) responses in [human] lymphocyte populations which were previously primed in long-term, 1-way mixed lymphocyte reactions (MLR). The objective was to identify the genetic region responsible for this secondary mitogenic effect. Restimulation responses between unrelated and related individuals from a family with a recombinant between HLA-B and D produced similar results. In both cases responses were grouped into O, intermediate and positive. Restimulation was by 3 types of cell: those with HLA-D types compatible with the responder, those with HLA-D types specific to the primary stimulator, and those with HLA-D types of a 3rd-party cell. Compatible responses fell into the O category and the intermediate category, 3rd-party responses fell into the intermediate category, and specific responses fell into the positive category. HLA-D products evoked secondary mitogenic responses, while structures coded for by the HLA-A and B regions appeared to have no effect.