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Puumala virus, which causes nephropathia epidemica (NE), is the most prevalent hantavirus in Germany; bank voles serve as the main reservoir. During 2001–2007, most NE cases reported from Germany occurred in the southwestern state of Baden-Württemberg. We investigated the influence of bank vole habitats (beech forest, seed plants), vole food supply (beechnut mast), climate factors (winter and spring temperatures), and human population density on spatial and temporal occurrence of NE cases in Baden- Württemberg. Using Poisson-regression analyses, we found that all these factors influenced disease incidence. Furthermore, an independent trend of increasing incidence predicted that incidence will nearly double each year. The regression model explained 75% of the annual variation in NE incidence. The results suggest that environmental drivers lead to increasing incidence of NE infections in the southern part or even other parts of Germany.