To test for a role for the cellular prion protein (PrP c) in cell death, we used a PrP c‐binding peptide. Retinal explants from neonatal rats or mice were kept in vitro for 24 h, and anisomycin (ANI) was used to induce apoptosis. The peptide activated both cAMP/protein kinase A (PKA) and Erk pathways, and partially prevented cell death induced by ANI in explants from wild‐type rodents, but not from PrP c‐null mice. Neuroprotection was abolished by treatment with phosphatidylinositol‐specific phospholipase C, with human peptide 106–126, with certain antibodies to PrP c or with a PKA inhibitor, but not with a MEK/Erk inhibitor. In contrast, antibodies to PrP c that increased cAMP also induced neuroprotection. Thus, engagement of PrP c transduces neuroprotective signals through a cAMP/PKA‐dependent pathway. PrP c may function as a trophic receptor, the activation of which leads to a neuroprotective state.