Background: The incidence of West Nile virus (WNv) has remained high in the northern Great Plains compared to the rest of the United States. However, the reasons for the sustained high risk of WNv transmission in this region have not been determined. To assess the environmental drivers of WNv in the northern Great Plains, we analyzed the county-level spatial pattern of human cases during the 2003 epidemic across a seven-state region.

Methodology/principal findings: County-level data on WNv cases were examined using spatial cluster analysis, and were used to fit statistical models with weather, climate, and land use variables as predictors. In 2003 there was a single large cluster of elevated WNv risk encompassing North Dakota, South Dakota, and Nebraska along with portions of eastern Montana and Wyoming. The relative risk of WNv remained high within the boundaries of this cluster from 2004-2007. WNv incidence during the 2003 epidemic was found to have a stronger relationship with long-term climate patterns than with annual weather in either 2002 or 2003. WNv incidence increased with mean May-July temperature and had a unimodal relationship with total May-July precipitation. WNv incidence also increased with the percentage of irrigated cropland and with the percentage of the human population living in rural areas.

Conclusions/significance: The spatial pattern of WNv cases during the 2003 epidemic in the northern Great Plains was associated with both climatic gradients and land use patterns. These results were interpreted as evidence that environmental conditions across much of the northern Great Plains create a favorable ecological niche for Culex tarsalis, a particularly efficient vector of WNv. Further research is needed to determine the proximal causes of sustained WNv transmission and to enhance strategies for disease prevention.