Optimal proliferative response of T lymphocytes to purified protein derivative of tuberculin (PPD) in vitro requires that antigen be presented by autologous macrophages or allogeneic macrophages sharing HLA-D/DR determinants with the T cell donor. In some cases, however, T cells may respond to a limited extent to PPD in association with macrophages expressing different HLA-D/DR determinants. In this paper experiments are presented where various combinations of T cells and HLA-D/DR disparate macrophages were stimulated with PPD. We often found a stronger PPD-specific response in HLA-D/DR-incompatible combinations in which the macrophages carried HLA-DR antigens known from serological studies to be cross-reactive with those of the T cell donor than in combinations in which this was not the case. Thus, the cross-reactions detected by serology may sometimes be reflected on a functional level in T lymphocyte/macrophage cooperation.