The High Plains region is relatively high elevation (800-2000m) and dry (350-500 cm precipitation); intersected by few major rivers (Missouri, Platte, Arkansas, Pecos and their lesser tributaries); and largely characterized by short and long grass prairie with woodlands mainly associated with riparian habitats. West Nile virus appears to have entered the region along watercourses in 2001-2. In 2003 the region experienced a widespread epizootic that was associated with a large epidemic affecting both rural and urban/suburban residential areas. This was followed by reduced, but widespread WN virus transmission during 2004. Surveillance during this period indicates that Culex tarsalis and Culex pipiens are important vectors in the region, and that other species likely play a minor role in epizootic/epidemic transmission. Above average temperatures and precipitation patterns appear to be associated with transmission intensity. An index associating measures of vector density and infection rate with human risk will be presented.