We examine the relationship between hydrologic variability and the incidence of human disease associated with West Nile virus (WNV; family Flaviviridae, genus Flavivirus) infection (hereafter termed "human WN cases") in Colorado from 2002 to 2007. We find that local hydrologic conditions, as simulated by the Mosaic hydrology model, are associated with differences in human WN cases. In Colorado's eastern plains, wetter spring conditions and drier summer conditions predict human WN cases. In Colorado's western mountains, drier spring and summer conditions weakly predict human WN cases. These findings support two working hypotheses: (1) wet spring conditions increase the abundance of Culex tarsalis vectors in the plains, and (2) dry summer conditions, and respondent irrigational practices during such droughts, favor Cx. pipiens and Cx. tarsalis abundance throughout Colorado. Both of these processes potentially increase the local vector-to-host ratio, favoring WNV amplification among competent avian hosts and bridging to humans.