In this study, we compared hematopoietic stem cells and mast cells, using microarray expression analysis, and identified the cellular prion protein (PrP(C)) as a potentially novel marker of mast cells. On further investigation, we found that PrP(C) is expressed on the surface of human and mouse mast cells, is rapidly released by mast cells upon activation, and is released in response to mast cell-dependent allergic inflammation in vivo. Because mast cells are long lived and traffic to the brain and central nervous system, our observations could have important implications for the transmission and pathology of prion diseases.