Professional antigen-presenting cells (APCs) constitute a heterogeneous leukocyte population that controls T cell induction. Experimental animal studies have delineated the principal APCs of the airway mucosa as a network of intraepithelial dendritic cells (DCs). Whether the situation is comparable in the human airways is unknown. Here we performed a detailed characterization of putative APCs residing in the normal upper airway mucosa, employing confocal microscopy of whole-mount preparations combined with immunophenotyping. A dense network of human leukocyte antigen-DR+ cells with dendritic morphology was found not only in the epithelium (median number, 573/mm2), but also in the lamina propria. In both compartments these cells could be divided into two main populations based on their phenotypic characteristics: the majority expressed a macrophage-like phenotype (CD11b+CD14+CD64+CD68+RFD7+), whereas the smaller population was predominantly constituted by CD1c+CD11c+ immature DCs intermingled with the former. These immature DCs corresponded to the lineage-negative human leukocyte antigen-DR+CD11c+ DC subset present in peripheral blood. Thus, the human upper airway mucosa, in contrast to the rodent counterpart, contains a heterogeneous dense network of dendritic APCs consisting of spatially closely related macrophages and DCs. How these two cell populations regulate the tone of the local adaptive immune system should be the focus of further studies.