The central nervous system (CNS) represents an important target organ of the phocine distemper virus (PDV). The aim of the present study was to characterize pathological changes in the CNS of harbor seals suffering from natural PDV-infection. The distribution of virus protein and mRNA was investigated by immunohistochemistry (IHC) and in situ hybridization, respectively. In addition, inflammatory and glial cells were characterized by IHC. Polioencephalitis with glial activation, neuronal death and perivascular mononuclear infiltrations in the cerebral cortex was the main histopathological finding. Inflammatory responses, dominated by CD3+ T-cells and activated microglia/macrophages were associated with a prominent MHC-II upregulation within the CNS. Viral protein was found predominantly in neurofilament-expressing neurons within inflamed areas as demonstrated by immunohistochemical double-labeling. Morbillivirus nucleo-, phospho-, matrix-, fusion- and hemagglutinin-proteins were found in CNS-lesions. The expressions of viral matrix- and fusion-proteins were reduced in severely inflamed plaques. Comparison of viral protein and mRNA expression revealed a diminished amount of viral phosphoprotein preferentially associated with perivascular inflammation. In summary, CNS-lesions in PDV-infected seals are similar to canine distemper virus-induced acute polioencephalitis in dogs and measles virus inclusion body polioencephalitis in men, respectively.