Usutu virus (USUV), a mosquito-borne flavivirus of the Japanese encephalitis virus group has been responsible for avian mortality in Austria since 2001. In the present study, the neuropathogenicity and neuroinvasiveness of USUV for 1-week-old suckling mice was investigated. After intraperitoneal inoculation, clinical signs like depression, disorientation, paraplegia, paralysis and coma were observed between 6 and 11 days post infection. Histologically, there was widespread neuronal apoptosis especially in the brain stem. Inflammatory infiltrates were scarce. Apoptosis was also present in white matter of cerebellum, medulla and spinal cord, and was frequently accompanied by primary demyelination. While apoptosis of neurons was clearly associated with presence of viral signals, the cause of apoptosis of white matter cells was more ambiguous. However, focal immunostaining was found in the white matter, especially in the spinal cord. As with all flaviviruses, USUV proved to be neuropathogenic for mice. In contrast to other flaviviruses, neuroinvasion occurred only in animals that were not older than 1 week at the time of inoculation. While neuronal apoptosis is a general aspect of flavivirus pathogenicity, demyelination seems to be a unique feature of USUV infection.