AbstractTick-borne encephalitis (TBE) vaccination coverage remains low in Germany. Our case–control study (2018–2020) aimed to examine reasons for low vaccine uptake, vaccine effectiveness (VE), and vaccine breakthrough infections (VBIs). Telephone interviews (581 cases, 975 matched controls) covered vaccinations, vaccination barriers, and confounders identified with directed acyclic graphs. Multivariable logistic regression determined VE as 1—odds ratio with 95% confidence intervals (CI). We additionally calculated VE with the Screening method using routine surveillance and vaccination coverage data. Main vaccination barriers were poor risk perception and fear of adverse events. VE was 96.6% (95% CI 93.7–98.2) for ≥ 3 doses and manufacturer-recommended dosing intervals. Without boosters, VE after ≥ 3 doses at ≤ 10 years was 91.2% (95% CI 82.7–95.6). VE was similar for homologous/heterologous vaccination. Utilising routine surveillance data, VE was comparable (≥ 3 doses: 92.8%). VBIs (n = 17, 2.9% of cases) were older, had more comorbidities and higher severity than unvaccinated cases. However, only few VBIs were diagnostically confirmed; 57% of re-tested vaccinated cases (≥ 1 dose, n = 54) proved false positive. To increase TBE vaccine uptake, communication efforts should address complacency and increase confidence in the vaccines’ safety. The observed duration of high VE may inform decision-makers to consider extending booster intervals to 10 years.