We recently found that deletion of the Asn-linked carbohydrate (CHO) at residue 197 of Syrian hamster (SHa) PrP(C) while retaining the CHO at Asn 181 has a profound effect on which population of neurons are targeted for conversion of SHaPrP(C) to SHaPrP(Sc) in transgenic (Tg) mice inoculated with scrapie prions. We hypothesized that selective targeting of neuronal populations is determined by cell-specific differences in the affinity of an infecting PrP(Sc) (prion) for PrP(C) and that the affinity might be modulated by nerve cell-specific differences in PrP(C) glycosylation. Here we tested this hypothesis by assessing whether or not each brain region in Syrian hamsters synthesizes different PrP(C) glycoforms, as inferred from 2D-gel electrophoresis. Reproducible differences in the number and isoelectric point of PrP(C) charge isomers were found as a function of brain region. The results of this study support the hypothesis that the PrP(Sc) accumulation and the vacuolation pattern phenotypes in the brain are governed by neuron-specific differences in PrP(C) glycoforms.