Tick-borne encephalitis is a viral disease affecting the central nervous system. It is endemic in Switzerland with 200-250 notified cases annually. Active immunization is effective for persons in all age groups. Vaccine failure is rare, in particular after a completed vaccination course. Here, we describe the case of 67-year-old man with a fatal outcome despite vaccination. The diagnosis was confirmed by extensive postmortem analyses. The diagnostic challenges of vaccine failure in tick-borne encephalitis and the dynamics of the immune response in vaccination breakthrough are discussed.