The spatial distribution of human cases of tick-borne diseases is probably determined by a combination of biological and socioeconomic factors. A zoonotic tick-borne pathogen, Ehrlichia chaffeensis, is increasing in human incidence in the USA. In this study, the spatial patterns of probable and confirmed E. chaffeensis-associated cases of ehrlichiosis from 2000 to 2011 were investigated at the zip-code level in Missouri. We applied spatial statistics, including global and local regression models, to investigate the biological and socioeconomic factors associated with human incidence. Our analysis confirms that the distribution of ehrlichiosis in Missouri is non-random, with numerous clusters of high incidence. Furthermore, we identified significant, but spatially variable, associations between incidence and both biological and socioeconomic factors, including a positive association with reservoir host density and a negative association with human population density. Improved understanding of local variation in these spatial factors may facilitate targeted interventions by public health authorities.