The national resurgence of human West Nile virus (WNV) disease in 2012 raised questions about the factors responsible for WNV outbreaks. Interannual climatic variations may influence WNV amplification and transmission to humans through multiple pathways, including mosquito breeding habitats, gonotrophic cycles, extrinsic incubation, avian communities, and human behavior. We examined the influences of temperature and precipitation anomalies on interannual variation in human WNV cases in three regions of the United States. There were consistent positive influences of winter temperatures, weaker and more variable positive effects of spring and summer temperatures, and highly variable precipitation effects that ranged from positive to negative. The overwintering period may be a particularly important climatic constraint on the dynamics of WNV in cold-temperate regions of North America. Geographic differences in the seasonal timing and relative importance of climatic drivers of WNV risk likely reflect underlying variability in key ecological and social characteristics.