Background: Tick-borne encephalitis (TBE) is a viral infectious disease caused by tick-borne encephalitis virus (TBEV). TBEV infection is responsible for a variety of clinical manifestations ranging from mild fever to severe neurological illness. Genetic factors involved in the host response to TBEV that may potentially play a role in the severity of the disease are still poorly understood. In this study, using whole-exome sequencing, we aimed to identify genetic variants and genes associated with severe forms of TBE as well as biological pathways through which the identified variants may influence the severity of the disease. Results: Whole-exome sequencing data analysis was performed on 22 Russian patients with severe forms of TBE and 17 Russian individuals from the control group. We identified 2407 candidate genes harboring rare, potentially pathogenic variants in exomes of patients with TBE and not containing any rare, potentially pathogenic variants in exomes of individuals from the control group. According to DAVID tool, this set of 2407 genes was enriched with genes involved in extracellular matrix proteoglycans pathway and genes encoding proteins located at the cell periphery. A total of 154 genes/proteins from these functional groups have been shown to be involved in protein-protein interactions (PPIs) with the known candidate genes/proteins extracted from TBEVHostDB database. By ranking these genes according to the number of rare harmful minor alleles, we identified two genes (MSR1 and LMO7), harboring five minor alleles, and three genes (FLNA, PALLD, PKD1) harboring four minor alleles. When considering genes harboring genetic variants associated with severe forms of TBE at the suggestive P-value < 0.01, 46 genes containing harmful variants were identified. Out of these 46 genes, eight (MAP4, WDFY4, ACTRT2, KLHL25, MAP2K3, MBD1, OR10J1, and OR2T34) were additionally found among genes containing rare pathogenic variants identified in patients with TBE; and five genes (WDFY4, ALK, MAP4, BNIPL, EPPK1) were found to encode proteins that are involved in PPIs with proteins encoded by genes from TBEVHostDB. Three genes out of five (MAP4, EPPK1, ALK) were found to encode proteins located at cell periphery. Conclusions: Whole-exome sequencing followed by systems biology approach enabled to identify eight candidate genes (MAP4, WDFY4, ACTRT2, KLHL25, MAP2K3, MBD1, OR10J1, and OR2T34) that can potentially determine predisposition to severe forms of TBE. Analyses of the genetic risk factors for severe forms of TBE revealed a significant enrichment with genes controlling extracellular matrix proteoglycans pathway as well as genes encoding components of cell periphery.