The mechanisms involved in prion neurotoxicity are unclear, and therapies preventing accumulation of PrP^Sc, the disease-associated form of prion protein (PrP), do not significantly prolong survival in mice with central nervous system prion infection. We found that depleting endogenous neuronal PrP^c in mice with established neuroinvasive prion infection reversed early spongiform change and prevented neuronal loss and progression to clinical disease. This occurred despite the accumulation of extraneuronal PrP^Sc to levels seen in terminally ill wild-type animals. Thus, the propagation of nonneuronal PrP^Sc is not pathogenic, but arresting the continued conversion of PrP^c to PrP^Sc within neurons during scrapie infection prevents prion neurotoxicity.