Geographic information systems combined with methods of spatial analysis provide powerful new tools for understanding the epidemiology of diseases and for improving disease prevention and control. In this study, the spatial distribution of a newly recognized tick-borne disease, human granulocytic ehrlichiosis (HGE), was investigated for nonrandom patterns and clusters in an area known to be endemic for tick-borne diseases. Analysis of confirmed cases of HGE identified in 1997–2000 in a 12-town area around Lyme, Connecticut, showed that HGE infections are not distributed randomly. Smoothed HGE incidence was higher around the mouth of the Connecticut River and lower to the north and west. Cluster analysis identified one area of increased HGE risk (relative risk=1.8, p=0.001). This study demonstrates the utility of geographic information systems and spatial analysis to clarify the epidemiology of HGE.