Nonlymphoid tissues from human fetuses ranging in age from 12 to 21 weeks' gestation were examined for the presence of HLA-DR (Ia)-positive cells. Immunoperoxidase staining of cryostat sections revealed Ia-positive cells with dendritic-like morphology, in kidney, heart, pancreas, and lung--but not in brain tissue. These Ia-bearing cells were present at 12 weeks' gestation, and by 21 weeks had increased to substantial numbers in all the organs tested, except for the brain, which remained negative. To further characterize the nature of these Ia-positive cells serial sections were studied with a panel of monoclonal antibodies (MAb) consisting of four reagents identifying monocyte/macrophages and two reagents staining lymphoid cells. The four anti-monocyte/macrophage MAb stained few if any cells in all the tissues examined. Lymphoid cells, as identified by anti-B-cell and anti-T-cell MAb, were also present in very low numbers. Additional studies using a double-staining technique provided direct evidence that the Ia-positive cells bear the human common leukocyte antigen detected by MAb T29 /33 and, with few exceptions, are negative for the macrophage antigen detected by MAb OKM1. The data suggest that nonlymphoid fetal tissues contain Ia-positive dendritic-like cells that are not monocyte/macrophage or lymphoid in origin. These Ia-bearing cells may be related to the dendritic cells found in lymphoid tissues, which are highly stimulatory in mixed leukocyte reactions and are thought to be responsible for the initiation of allograft rejection.