The observation that lymphocytes from two unrelated individuals could stimulate each other and induce T cell blast transformation in culture led to the demonstration that the antigens involved in this stimulation were genetically determined and inherited together with antigens of the HLA complex. Subsequent studies in a recombinant family confirmed that the stimulation seen in vitro was genetically controlled by a chromosomal region distinct from that controlling the serologically defined HLA-A, -B, and -C antigens. The phenotype frequency of the HLA-Dw determinants varies in different population groups. The assignment of HLA-Dw types is based on low proliferative responses to HLA-Dw compatible HTCs in MLC experiments, and is based on all DNVs obtained by a given responder, with all HTCs defining a particular specificity. The HLA-Dw determinants detected in primary mixed lymphocyte reaction behave as a single genetic series.