Ruffed grouse ( Bonasa umbellus) population numbers in Pennsylvania dramatically declined during the early 2000s and have subsequently remained depressed throughout much of the state. While this decline has been temporally associated with the presence of West Nile virus (WNV), lack of information on the WNV susceptibility of this popular game bird species has limited the ability to interpret the potential impacts of WNV. To address this knowledge gap, virologic, immunologic, pathologic, and clinical responses as well as protective effects of vaccination following experimental WNV inoculation in ruffed grouse were assessed. Four of 10 (40%) naive, WNV-inoculated grouse succumbed to infection within 8 days and had moderate mean peak viremia titers (10 plaque-forming units [PFU]/ml serum); severe necrotizing myocarditis with widespread, corresponding immunohistochemical labeling; and minimal encephalitis. Grouse that survived to the prescribed end point of 14 days postinoculation (6/10; 60%) had slightly lower mean peak viremia titers (10 PFU/ml serum), moderate myocardial lesions, and more widespread brain lesions with rare corresponding immunohistochemical labeling. Vaccinated, WNV-inoculated birds ( n = 5) had lower mean peak viremia titers (10 PFU/ml serum) and minimal lesions, and sham-inoculated, in-contact control birds ( n = 3) had no evidence of infection. All surviving, inoculated birds seroconverted, and WNV-specific antibodies were detectable in serum and Nobuto filter paper strip-eluted blood samples. These data suggest that WNV could serve as an additional population pressure on ruffed grouse in regions where transmission levels are high and WNV competent, ornithophilic vectors exist.