The transmission of West Nile virus (WNV) is strongly influenced by environmental factors. In France, two endemic areas for WNV have been identified: Camargue and Var. The objective of our study was to test whether landscape characteristics could be associated with the risk of endemic circulation of WNV in these two ecologically different areas. Equine serological data collected during outbreaks in Var (2003) and Camargue (2004) were used. Both areas were marked out in cells of 5 km(2), and data were aggregated for each cell. Sixteen cells, classified as "high" level viral circulation, and 28 cells, classified as "low" level viral circulation were used for the analysis. The Corine Land Cover database (European Environment Agency) was used to evaluate, for each geographic cell, the area covered by 12 land cover classes, as well as the value of 5 landscape metrics (patch richness and density, edge density, the Shannon's diversity index, and interspersion and juxtaposition index (IJI). Multivariate linear generalized regression showed that IJI as well as the surface covered by heterogeneous agricultural areas were significantly higher in high level WNV circulation cells than in low level ones (p = 0.01 and 0.05 respectively). Both variables are indicators of a complex spatial biotope configuration that may favor the co-existence of competent vectors and reservoir hosts: the structure of the landscape thus appeared as a key element in WNV circulation. An internal validation was performed and the model was used to compute a risk map for the French Mediterranean coast. Cells with a probability > 0.8 of having a high level of viral circulation were found near Aix-en-Provence, Beziers, and Perpignan, areas where no serological study has yet been conducted. Equine cases reported in 2006 were all located in the neighborhood of cells having a > 0.8 probability for high WNV circulation status.