OBJECTIVE: Type 1 and type 2 diabetes are characterized by an approximately 98 and approximately 65% loss of pancreatic beta-cells, respectively. Efforts to reverse either form of diabetes increasingly focus on the possibility of promoting beta-cell replacement and/or regeneration. Islet transplantation has been explored, but it does not provide long-term insulin independence. One possible source of beta-cell regeneration is hematopoietic stem cells. In mice, there are conflicting data as to whether hematopoietic stem cells contribute to pancreatic beta-cells. We sought to establish whether hematopoietic stem cells (derived from adult donors) transdifferentiate into pancreatic beta-cells in adult humans. RESEARCH DESIGN AND METHODS: We addressed this in 31 human pancreata obtained at autopsy from hematopoietic stem cell transplant recipients who had received their transplant from a donor of the opposite sex. RESULTS: Whereas some donor-derived cells were observed in the nonendocrine pancreata, no pancreatic beta-cells were identified that were derived from donor hematopoietic stem cells, including two cases with type 2 diabetes. CONCLUSIONS: We conclude that hematopoietic stem cells derived from adult donors contribute minimally to pancreatic beta-cells in nondiabetic adult humans. These data do not rule out the possibility that hematopoietic stem cells contribute to pancreatic beta-cells in childhood or in individuals with type 1 diabetes.