Cache-Valley (CV) virus, an arthropod-borne bunyavirus, recently has emerged as a significant veterinary pathogen causing infertility and congenital malformations in North American ruminants. To investigate the role of vector feeding on CV infection, adult mice were injected subcutaneously with CV, CV and vector thorax extract (a source of vector saliva), or CV into the site of intense, noninfected-mosquito feeding. Mice did not become infected after injection of CV or CV and vector saliva, nor did they produce antibodies to CV. However, injection of CV into sites of mosquito feeding resulted in viremia and production of anti-CV antibody by 2 wk after infection. This enhancement of CV infection resulted after feeding by Aedes triseriatus (Say), Ae. aegypti (L.), or Culex pipiens (L.). Enhancement occurred when injection was delayed up to 4 h after mosquito feeding, but it was not observed when virus injection was performed at a site distant from mosquito feeding. These results indicate that arbovirus infection may be enhanced by mosquito-vertebrate host interactions and that replication of arboviruses in arthropod vectors may not be responsible for increased virulence of infections mediated by infected arthropods. Enhanced CV infection in pregnant mice did not result in infertility or malformed pups, indicating that the mouse is not a suitable model to study CV-induced malformations.