Prion diseases result from conformational alteration of PrPC, a cell surface glycoprotein expressed in brain, spinal cord, and several peripheral tissues, into PrPSc, a protease-resistant isoform that is the principal component of infectious prion particles. Although a great deal is known about the pathogenic role of PrPSc, the physiological function of PrPC has remained a mystery. Several lines of evidence have recently suggested the possibility that PrPC may play a role in the metabolism of copper. To further investigate the interaction of PrPC and copper, we have analyzed the effect of this metal ion on the endocytic trafficking of PrPC in cultured neuroblastoma cells. We report here that copper rapidly and reversibly stimulates endocytosis of PrPC from the cell surface. This effect may be physiologically relevant and suggests the hypothesis that PrPC could serve as a recycling receptor for uptake of copper ions from the extracellular milieu.