Cellular prion protein (PrP C ) plays anti-apoptotic and anti-oxidative roles in apoptosis induced by serum deprivation in an immortalized prion protein gene (Prnp)-deficient neuronal cell line. The octapeptide repeat region (OR) and N-terminal half of the hydrophobic region (HR) of PrP C are indispensable for PrP C activity, but the mechanisms remain unclear. In the present study, elucidation of the mechanisms by which PrP C elicits the anti-oxidative activities was facilitated by evidence of stress-inducible protein 1 (STI1) mediating PrP C -dependent superoxide dismutase (SOD) activation. Immunoprecipitation revealed that PrP C was associated with STI1. The inhibitory peptides against PrP C –STI1 binding [STI1 pep.1 and PrP(113–132)] indicated toxic activity in PrP C -expressing cells by inhibiting SOD activity but not in Prnp −/− cells. Furthermore, OR and N-terminal half of the HR were required for the inhibitory effect of PrP(113–132) but not STI1 pep.1. These data are consistent with results established with a model where OR and N-terminal half of the HR mediate the action of STI1 upon cell survival and upregulation of SOD activity.