Dendritic cells (DC) are unique in their ability to present antigen to naive T cells, and therefore play a central role in the initiation of immune responses. Characterization of DC-specific genes may help to unravel the mechanism underlying their potent antigen presenting capacity. Here we describe the identification of a novel transcript, isolated by random sequencing of a cDNA library prepared from monocyte-derived DC, which we termed DC-specific transmembrane protein (DC-STAMP). DC-STAMP is specifically expressed by DC, and not in a panel of other leukocytes or non-hematopoietic cells. Interestingly, DC-STAMP was also detected in activated but not resting blood DC. The DC-STAMP transcript encodes a 470-amino acid protein containing seven putative transmembrane domains. Expression of a DC-STAMP-GFP fusion protein in 293 cells indicates that DC-STAMP is expressed at the cell surface, and has an intracellular C terminus. Surprisingly, no sequence homology was found with any other protein or multimembrane-spanning receptor. Therefore, we propose that DC-STAMP is a novel DC-specific multimembrane-spanning protein, representing a new group of transmembrane proteins.