Congenital or acquired cellular deficiencies in humans have the potential to reveal much about normal hematopoiesis and immune function. We show that a recently described syndrome of monocytopenia, B and NK lymphoid deficiency additionally includes the near absence of dendritic cells. Four subjects showed severe depletion of the peripheral blood HLA-DR⁺ lineage⁻ compartment, with virtually no CD123⁺ or CD11c⁺ dendritic cells (DCs) and very few CD14⁺ or CD16⁺ monocytes. The only remaining HLA-DR⁺ lineage⁻ cells were circulating CD34⁺ progenitor cells. Dermal CD14⁺ and CD1a⁺ DC were also absent, consistent with their dependence on blood-derived precursors. In contrast, epidermal Langerhans cells and tissue macrophages were largely preserved. Combined loss of peripheral DCs, monocytes, and B and NK lymphocytes was mirrored in the bone marrow by complete absence of multilymphoid progenitors and depletion of granulocyte-macrophage progenitors. Depletion of the HLA-DR⁺ peripheral blood compartment was associated with elevated serum fms-like tyrosine kinase ligand and reduced circulating CD4⁺CD25^hiFoxP3⁺ T cells, supporting a role for DC in T reg cell homeostasis.