West Nile virus (WNV) arrived in North America and spread rapidly through the western hemisphere. We present a series of tests to determine whether ecological factors are consistently associated with WNV transmission to humans. We analyzed human WNV cases in the states of Illinois, Indiana, and Ohio in 2002 and 2003, building ecological niche models to associate WNV case occurrences with ecological and environmental parameters. In essentially all tests, both within states, among states, between years, and across the region, we found high predictivity of WNV case distributions, suggesting that one or more elements in the WNV transmission cycle has a strong ecological determination. Areas in the geographic region included in this study predicted as suitable for WNV transmission tended to have lower values of the vegetation indices in the summer months, pointing to consistent ecological differences between suitable and unsuitable areas.