After several years of low West Nile virus (WNV) occurrence in the United States of America (USA), 2012 witnessed large outbreaks in several parts of the country. In order to understand the outbreak dynamics, spatial clustering and landscape, demographic and climatic associations with WNV occurrence were investigated at a regional level in the USA. Previous research has demonstrated that there are a handful of prominent WNV mosquito vectors with varying ecological requirements responsible for WNV transmission in the USA. Published range maps of these important vectors were georeferenced and used to define eight functional ecological regions in the coterminous USA. The number of human WNV cases and human populations by county were attained in order to calculate a WNV rate for each county in 2012. Additionally, a binary value (high/low) was calculated for each county based on whether the county WNV rate was above or below the rate for the region it fell in. Global Moran's I and Anselin Local Moran's I statistics of spatial association were used per region to examine and visualize clustering of the WNV rate and the high/low rating. Spatial data on landscape, demographic and climatic variables were compiled and derived from a variety of sources and then investigated in relation to human WNV using both Spearman rho correlation coefficients and Poisson regression models. Findings demonstrated significant spatial clustering of WNV and substantial inter-regional differences in relationships between WNV occurrence and landscape, demographic and climatically related variables. The regional associations were consistent with the ecologies of the dominant vectors for those regions. The large outbreak in the Southeast region was preceded by higher than normal winter and spring precipitation followed by dry and hot conditions in the summer.