Understanding the physiological function of the cellular prion (PrP^c) depends on the investigation of PrP^c-interacting proteins. Stress-inducible protein 1 (STI1) is a specific PrP^c ligand that promotes neuroprotection of retinal neurons through cAMP-dependent protein kinase A (PKA). Here, we examined the signaling pathways and functional consequences of the PrP^c interaction with STI1 in hippocampal neurons. Both PrP^c and STI1 are abundantly expressed and highly colocalized in the hippocampus in situ, indicating that they can interact in vivo. Recombinant STI1 (His₆-STI1) added to hippocampal cultures interacts with PrP^c at the neuronal surface and elicits neuritogenesis in wild-type neurons but not in PrP^c-null cells. This effect was abolished by antibodies against either PrP^c or STI1 and was dependent on the STI1 domain that binds PrP^c. Binding of these proteins induced the phosphorylation/activation of the mitogen-activated protein kinase, which was essential for STI1-promoted neuritogenesis. His₆-STI1, but not its counterpart lacking the PrP^c binding site, prevented cell death via PKA activation. These results demonstrate that two parallel effects of the PrP^c–STI1 interaction, neuritogenesis and neuroprotection, are mediated by distinct signaling pathways.