Tick-borne encephalitis (TBE) virus is endemic in large parts of Europe and Central and Eastern Asia and causes more thanurological disease in humans. It is closely related to themosquito-borne yellow fever, dengue, Japaneseencephalitis, and West Nile viruses, and vaccination with an inactivated whole-virus vaccine can effectively prevent clinical disease. Neutralizing antibodies are directed to the viral envelope protein (E) and an accepted correlate of immunity. However, dataon the specificities of CD4 T cells that recognize epitopes in the viral structural proteins and thus can provide direct help to theB cells producing E-specific antibodies are lacking. We therefore conducted a study on the CD4 T cell response against the virion proteins in vaccinated people in comparison to TBE patients. The data obtained with overlapping peptides in interleukin-2(IL-2) enzyme-linked immunosorbent spot (ELISpot) assays were analyzed in relation to the three-dimensional structures of thecapsid (C) and E proteins as wellas to epitope predictions based on major histocompatibility complex (MHC) class II peptideaffinities. In the C protein, eptides corresponding to two out of four alpha helices dominated the response in both vaccinees andpatients, whereas in the E protein concordance of immunodominance was restricted to peptides of a single domain (domain III).Epitope predictions were much better for C than for E and were especially erroneous for the transmembrane regions. Our dataprovide evidence for a strong impact of protein structural features that influence peptide processing, contributing to the discrepancies observedbetween experimentally determined and computer-predicted CD4 T cell epitopes.