Background: The Western Tick-borne encephalitis (TBE) virus often causes devastating or lethal disease. In Europe, the number of human TBE cases has increased dramatically over the last decade, risk areas are expanding and new foci are being discovered every year. The early localisation of new TBE foci and the identification of the main risk factors associated with disease emergence represent a priority for the public health community. Although a number of socio-economic parameters have been suggested to explain TBE upsurges in eastern Europe, the principal driving factors in relatively stable western European countries have not been identified. Methodology/Principal Findings: In this paper, we analyse the correlation between the upsurge of TBE in 17 alpine provinces in northern Italy from 1992 to 2006 with climatic variables, forest structure (as a proxy for small mammal reservoir host abundance), and abundance of the principal large vertebrate tick host (roe deer), using datasets available for the last 40 years. No significant differences between the pattern of changes in climatic variables in provinces where TBE has emerged compared to provinces were no clinical TBE cases have been observed to date. Instead, the best model for explaining the increase in TBE incidence in humans in this area include changes in forest structure, in particular the ratio of coppice to high stand forest, and the density of roe deer. Conclusion/Significance: Substantial changes in vegetation structure that improve habitat suitability for the main TB
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