Prions are thought to consist of infectious proteins that cause transmissible spongiform encephalopathies¹. According to overwhelming evidence, the pathogenic prion protein PrP^Sc converts its host encoded isoform PrP^c into insoluble aggregates of PrP^Sc, concomitant with pathological modifications (for review, see refs. 1–3). Although the physiological role of PrP^c is poorly understood⁴, studies with PrP knockout mice demonstrated that PrP^c is required for the development of prion diseases⁵. Using the yeast two-hybrid technology in Saccharomyces cerevisiae, we identified the 37-kDa laminin receptor precursor (LRP) as interacting with the cellular prion protein PrP^c. Mapping analysis of the LRP–PrP interaction site in S. cerevisiae revealed that PrP and laminin share the same binding domain (amino acids 161 to 180)⁶ on LRP. The LRP–PrP interaction was confirmed in vivo in insect (Sf9) and mammalian cells (COS-7). The LRP level was increased in scrapie-infected murine N₂a cells and in brain and spleen of scrapie-infected mice. In contrast, the LRP concentration was not significantly altered in these organs from mice infected with the bovine spongiform encephalopathic agent (BSE), which have a lower PrP^Sc accumulation. LRP levels, however, were dramatically increased in brain and pancreas, slightly increased in the spleen and not altered in the liver of scrapie-infected hamsters. These data show that enhanced LRP concentrations are correlated with PrP^Sc accumulation in organs from mice and hamsters. The laminin receptor precursor, which is highly conserved among mammals and is located on the cell surface, may act as a receptor or co-receptor for the prion protein on mammalian cells.