Mammalian prions are unconventional infectious agents that invade and replicate in an organism by recruiting a normal form of a prion protein (PrP^C) and converting it into misfolded, disease-associated state referred to as PrP^Sc. PrP^C is posttranslationally modified with two N-linked glycans. Prion strains replicate by selecting substrates from a large pool of PrP^C sialoglycoforms expressed by a host. Brain regions have different vulnerability to prion infection, however, molecular mechanisms underlying selective vulnerability is not well understood. Toward addressing this question, the current study looked into a possibility that sialylation of PrP^Sc might be involved in defining selective vulnerability of brain regions. The current work found that in 22L -infected animals, PrP^Sc is indeed sialylated in a region dependent manner. PrP^Sc in hippocampus and cortex was more sialylated than PrP^Sc from thalamus and stem. Similar trends were also observed in brain materials from RML- and ME7-infected animals. The current study established that PrP^Sc sialylation status is indeed region-specific. Together with previous studies demonstrating that low sialylation status accelerates prion replication, this work suggests that high vulnerability of certain brain region to prion infection could be attributed to their low sialylation status.