Background The etiology of Parkinson's disease (PD) remains unknown. To approach the issue of PD's risk factors from a new perspective, we hypothesized that coupling the geographic distribution of PD with spatial statistics may provide new insights into environmental epidemiology research. The aim of this case-control study was to examine the spatial dependence of PD prevalence in the Canton of Geneva, Switzerland (population=474,211). Methods PD cases were identified through Geneva University Hospitals, private neurologists and nursing homes medical records (n=1,115). Controls derived from a population-based study (n=12,614) and a comprehensive population census dataset (n=237,771). All individuals were geographically localized based on their place of residence. Spatial Getis-Ord Gi* statistics were used to identify clusters of high versus low disease prevalence. Confounder-adjustment was performed for age, sex, nationality and income. Tukey's honestly significant difference was used to determine whether nitrogen dioxide and particulate matters PM10 concentrations were different within PD hotspots, coldspots or neutral areas. Results Confounder-adjustment greatly reduced greatly the spatial association. Characteristics of the geographic space influenced PD prevalence in 6% of patients. PD hotspots were concentrated in the urban centre. There was a significant difference in mean annual nitrogen dioxide and PM10 levels (+3.6 μg/m3 [p<0.001] and +0.63 μg/m3 [p<0.001] respectively) between PD hotspots and coldspots. Conclusion PD prevalence exhibited a spatial dependence for a small but significant proportion of patients. A positive association was detected between PD clusters and air pollution. Our data emphasize the multifactorial nature of PD and support a link between PD and air pollution.