The major objective of this research was to further explore the pathogenesis of West Nile virus (WNV) in wild birds. Since it was first recognized in the United States in 1999, WNV has caused widespread mortality in birds. However, marked differences in species susceptibility have been reported. Previous studies have suggested that macrophages may be a major target of the virus. Consequently, it was hypothesized that differences in macrophage function would explain differences in species susceptibility. Specific aims included identification of susceptible species through passive surveillance, comparison of two different diagnostic methods (immunohistochemistry and virus isolation) for detection of WNV, description of gross and histopathologic lesions in naturally and experimentally infected birds, characterization of the distribution of virus or viral antigen in tissues, description of viral kinetics in vitro and in vivo, and measurement of inflammatory mediators produced by macrophages in vitro and in vivo.Passive surveillance suggested that corvids (crows and jays) were highly susceptible to infection and experienced high mortality. Other species such as rock doves had very low mortality. Both immunohistochemistry and virus isolation were effective in diagnosis of WNV, and there was greater than 90% agreement between the two tests. Histologic lesions were often absent or nonspecific, and lesions did not correlate with presence or amount of viral antigen. Raptorial species were examined in greater detail using histopathology, virus isolation, and immunohistochemistry. In raptors, WNV was primarily cardio- and neurotropic. Significant differences were noted between hawks and owls with owls tending to be less severely affected. Red-tailed Hawks, Coopers Hawks, and Sharp-shinned Hawks were more commonly affected than other species.