Prions are composed of an isoform of a normal sialoglycoprotein called PrP c, whose physiological role has been under investigation, with focus on the screening for ligands. Our group described a membrane 66 kDa PrP c‐binding protein with the aid of antibodies against a peptide deduced by complementary hydropathy. Using these antibodies in western blots from two‐dimensional protein gels followed by sequencing the specific spot, we have now identified the molecule as stress‐inducible protein 1 (STI1). We show that this protein is also found at the cell membrane besides the cytoplasm. Both proteins interact in a specific and high affinity manner with a K d of 10− 7 M. The interaction sites were mapped to amino acids 113–128 from PrP c and 230–245 from STI1. Cell surface binding and pull‐down experiments showed that recombinant PrP c binds to cellular STI1, and co‐immunoprecipitation assays strongly suggest that both proteins are associated in vivo. Moreover, PrP c interaction with either STI1 or with the peptide we found that represents the binding domain in STI1 induce neuropro tective signals that rescue cells from apoptosis.