Prion diseases are transmissible and fatal neurodegenerative disorders which involve infiltration and activation of mononuclear phagocytes at the brain lesions. A 20-aa acid fragment of the human cellular prion protein, PrP 106–126, was reported to mimic the biological activity of the pathologic isoform of prion and activates mononuclear phagocytes. The cell surface receptor (s) mediating the activity of PrP 106–126 is unknown. In this study, we show that PrP 106–126 is chemotactic for human monocytes through the use of a G protein-coupled receptor formyl peptide receptor-like 1 (FPRL1), which has been reported to interact with a diverse array of exogenous or endogenous ligands. Upon stimulation by PrP 106–126, FPRL1 underwent a rapid internalization and, furthermore, PrP 106–126 enhanced monocyte production of proinflammatory cytokines, which was inhibited by pertussis toxin. Thus, FPRL1 may act as a “pattern recognition” receptor that interacts with multiple pathologic agents and may be involved in the proinflammatory process of prion diseases.