BackgroundBunyavirus infections, including those caused by Bunyamwera serogroup orthobunyaviruses, represent a significant and yet likely still vastly underappreciated cause of mild to moderate human febrile infections. In severe cases, these infections can also cause neurological disease, particularly meningitis and encephalitis, and infection can even be fatal. However, with a few exceptions, information regarding the mechanisms underlying the neuroinvasion and neuropathogenesis of such infections is limited. This is due in part to a lack of animal models to facilitate such studies.Methodology/Principal findingsIn an effort to develop an immunocompetent model of infection with Bunyamwera serogroup orthobunyaviruses, we infected 4-6-week-old female hamsters via either the intraperitoneal or subcutaneous route with 106pfu/animal of Bunyamwera virus (BUNV), Batai virus or Ngari virus. Only BUNV infection resulted in clinical disease, which was characterized by weight loss, lethargy and neurological signs (i.e. tremor of the head or limbs, loss of righting reflex, “waltzing”). While symptoms were of similar severity for both routes, they occurred more frequently following subcutaneous inoculation. Consistent with these clinical signs, both antigen staining and histopathological abnormalities were found extensively throughout the brain.Conclusions/SignificanceThe reported hamster model of BUNV infection provides a new tool for studying orthobunyavirus infection, and particularly neuroinvasion and the development of neuropathology. This model is particularly significant because it makes use of immunologically competent animals and relies on a subcutaneous inoculation route that more closely mimics the natural infection route for arboviruses, thereby providing a more authentic cellular and immunological context at the initial site of infection.