A hamster model infected with a New York crow brain isolate of West Nile virus (WNV) was characterized for evaluating potential antiviral therapies. Older hamsters (7-11 weeks old) had a lower mortality of approximately 50% and more apparent disease signs as compared to >90% mortality in younger hamsters and mice. Disease signs such as limb strength, lacrimation, front limb tremors, somnolence, and deficiencies in neurological responses were noted at different times after viral injection. Weight loss was a marker for WNV disease signs, whereas, the ability to climb up an inclined ramp was associated with whether the animals survived the disease or died. Infectious WNV assays performed on tissues from hamsters during development of the infection indicated that viral titers peaked first in plasma, but that titers were eventually highest in kidney tissue. Viral titers achieved maximal levels in brain tissue on 6 dpi, which was 1-2 days before strong neurological signs and death started to occur. Maximal spleen and plasma titers were achieved sooner in young hamsters as compared with older hamsters, which correlated with increased susceptibility. To test the hypothesis that older hamsters would be more sensitive for identifying antiviral effects, Infergen, a consensus human interferon-alpha highly active against WNV in cell culture, was administered subcutaneously to older and younger hamsters beginning on 2 dpi. The effects of Infergen on weight change, survival, and climbing ability of infected animals were more apparent in older hamsters than in younger hamsters. The use of older hamsters is another WNV-infectious model, in addition to mice, for evaluating potential antiviral therapies.