Eliminating infected female mosquitoes by aerial applications of ultra-low volume adulticides is the intervention strategy currently recommended to interrupt the epidemic transmission of encephalitis viruses, including West Nile. The current research optimized pyrethrin formulations and evaluated their efficacy in the desert environment of the Coachella Valley, Riverside County, California. After seven trials during 2004, a 1:2 by volume mixture of Pyrenone 25-5 in BVA oil optimized particle size, droplet descent to ground level, and kill of sentinel mosquitoes. Three subsequent experiments used 3 aerial applications of the 1:2 Pyrenone 25-5:BVA oil mixture on alternate nights to suppress Culex tarsalis Coquillett host-seeking abundance over a 1-square-mile target area. Mortality patterns among caged sentinel mosquitoes varied among sites and replicate sprays, indicating variable particle dispersion at ground level within the target area. In addition, mortality was observed for sentinels up to 1 mile downwind from the target area, indicating considerable particle drift. Geometric mean abundance of host-seeking Cx. tarsalis females collected at dry ice–baited traps within each of 3 sprayed and 2 unsprayed negative control strata varied similarly over time, indicating that our sprays minimally impacted the target population or that drift combined with other factors led to widespread area control. Experiments during March and June when recruitment rates were minimal showed general area-wide suppression of abundance following spray, whereas an experiment during September when recruitment rates were high from newly flooded marshes failed to prevent an area-wide increase in abundance. Clearly additional research is needed to standardize the efficacy of aerial applications of pyrethrins in hot dry desert environments.