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Abstract Humans have greatly altered earth’s terrestrial water cycle with the majority of fresh water being used for agriculture. Irrigation changes spatial and temporal water availability and alters mosquito abundance and phenology. Previous studies evaluating the effect of irrigation on mosquito abundance and mosquito-borne disease have shown inconsistent results and little is known about the effect of irrigation on variability in mosquito abundance. We examined the effect of irrigation, climate and land cover on mosquito abundance and human West Nile virus (WNV) disease cases across California. Irrigation made up nearly a third of total water inputs, and exceeded precipitation in some regions. Abundance of two key vectors of several arboviruses, including WNV,Culex tarsalisand the Culex pipienscomplex, increased 17–21-fold with irrigation. Irrigation reduced seasonal variability inC. tarsalisabundance by 36.1%. Human WNV incidence increased with irrigation, which explained more than a third (34.2%) of the variation in WNV incidence among California counties. These results suggest that irrigation can increase and decouple mosquito populations from natural precipitation variability, resulting in sustained and increased disease burdens. Shifts in precipitation due to climate change are likely to result in increased irrigation in many arid regions which could increase mosquito populations and disease.