Cellular prion protein (PrP(C)) is a glycophosphatidylinositol (GPI)-anchored protein, of unknown function, found in a number of tissues throughout the body, including several blood components of which platelets constitute the largest reservoir in humans. It is widely believed that a misfolded, protease-resistant form of PrP(C), PrP(Sc), is responsible for the transmissible spongiform encephalopathy (TSE) group of fatal neurodegenerative diseases. Although the pathogenesis of TSEs is poorly understood, it is known that PrP(C) must be present in order for the disease to progress; thus, it is important to determine the physiologic function of PrP(C). Resolving the location of PrP(C) in blood will provide valuable clues as to its function. PrP(C) was previously shown to be on the alpha granule membrane of resting platelets. In the current study platelet activation led to the transient expression of PrP(C) on the platelet surface and its subsequent release on both microvesicles and exosomes. The presence of PrP(C) on platelet-derived exosomes suggests a possible mechanism for PrP(C) transport in blood and for cell-to-cell transmission.