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The Region of Central Macedonia (RCM) in Northern Greece recorded the highest number of human West Nile virus (WNV) infections in Greece, despite considerable local mosquito control actions. We examined spatial patterns and associations of mosquito levels, infected mosquito levels, and WNV human cases (WNVhc) across the municipalities of this region over the period 2010–2023 and linked it with climatic characteristics. We combined novel entomological and available epidemiological and climate data for the RCM, aggregated at the municipality level and used Local and Global Moran's I index to assess spatial associations of mosquito levels, infected mosquito levels, and WNVhc. We identified areas with strong interdependencies between adjacent municipalities in the Western part of the region. Furthermore, we employed a Generalized Linear Mixed Model to first, identify the factors driving the observed levels of mosquitoes, infected mosquitoes and WNVhc and second, estimate the influence of climatic features on the observed levels. This modeling approach indicates a strong dependence of the mosquito levels on the temperatures in winter and spring and the total precipitation in early spring, while virus circulation relies on the temperatures of late spring and summer. Our findings highlight the significant influence of climatic factors on mosquito populations (∼60 % explained variance) and the incidence of WNV human cases (∼40 % explained variance), while the unexplained ∼40 % of the variance suggests that targeted interventions and enhanced surveillance in identified hot-spots can enhance public health response.