During the last 30 years, the number of reported TBE cases in Europe has increased by more than 193%, despite two effective TBE vaccines (FSME Immune and Encepur) being available. The raison for this increase is manifold: e.g., emergence of new endemic areas, increased awareness and testing, besides changes in working and leisure time activities that have increased exposure to the TBE virus. Licensure of TBE vaccines are based on clinical studies demonstrating seroconversion, geometric mean antibody titers and seropersistence, while population-based vaccine effectiveness (VE) has so far only been performed in Austria. This country has an extremely high TBE vaccine coverage (at least one injection) and VE was calculated ≥90% for all age groups. A study has been conducted to investigate the VE of TBE vaccination in Germany and Latvia for the 12-year period from 2007 to 2018.