The expression of HLA-DR antigens in human fetal pancreas tissue was studied using four independently derived monoclonal antibodies recognizing nonpolymorphic HLA-DR antigens. Immunoperoxidase staining of frozen sections revealed numerous DR-antigen-positive cells. Two major cell types could be distinguished. Large, strongly DR-positive cells with dendritic morphology were distributed throughout the dendritic morphology were distributed throughout the pancreatic parenchyma and interstitial connective tissue. Dual staining of DR antigens and insulin using a two-color immunoperoxidase technique clearly showed that some of these DR-positive dendritic cells were located within and in close association with insulin-producing islets. Also observed as a regular feature of fetal pancreas tissue sections were large clusters of DR-positive cells with lymphoid morphology. Positive staining of many cells within these clusters with monoclonal antibodies against T-cell marker (Leu-1) and T-cell subset markers (Leu-2 and -3) supported their classification as lymphoid cells. In contrast, no positive staining with anti-T-cell antibodies was observed outside of lymphoid cell clusters, confirming the distinction between these cells and the DR-positive cells distributed throughout the pancreas. The presence of other DR-bearing cell types in fetal pancreas could not be excluded, but most endothelial cells appeared to be DR-negative. The demonstration of numerous DR-bearing cells associated with fetal pancreas tissue may require that we alter our views on DR-antigen ontogeny and develop new strategies for fetal pancreas transplantation.