Numerous hypotheses have been proposed to explain the end Pleistocene extinction of large bodied mammals. The disease hypothesis attributes the extinction to the arrival of a novel ‘hyperdisease’ brought by immigrating aboriginal humans. However, until West Nile virus (WNV) invaded the United States, no known disease met the criteria of a hyperdisease. We evaluate the disease hypothesis using WNV in the United States as a model system. We show that WNV is size-biased in its infection of North America birds, but is unlikely to result in an extinction similar to that of the end Pleistocene. WNV infects birds more uniformly across the body size spectrum than extinctions did across mammals and is not size-biased within orders. Our study explores the potential impact of WNV on bird populations and provides no support for disease as a causal mechanism for the end Pleistocene megafaunal extinction.