The Siberian subtype of the virus of tick-borne encephalitis (TBE), which is predominant in Russia, constantly circulated in its eastern European regions in 1943-2003 and in the Urals and West and East Siberia in 1960-2003. This subtype is transmitted by two types of ticks: Ixodes persulcatus and I. ricinis. Changes were not found in the structure of viral populations at the peak and drop of the incidence of TBE. There was new evidence on the genetic heterogenicity of the Siberian subtype: in addition to the strains containing histidine (H) or glutamine (Q) in the position of 234 of protein E gene, there were strains having tyrosine (V). There were differences in the eastern European and Asian populations of the Siberian subtype. The strains with labeled amino acids of H and Q amounted to 87.1 and 3.2% in the eastern European population and 60 and 40% in the Asian population, respectively. The eastern European strains with labeled amino acid of H differed from the same Asian strains in the level of nucleotide replacements in the studied E gene fragment. The strains containing tyrosine in position 234 were found only in the eastern European population. Sixty-two cases of TBE were analyzed, which showed a significantly established role of a certain subtype. The Siberian and Far Eastern subtypes in the area of joint circulation were found to cause the whole spectrum of infection manifestations from unapparent to severe focal forms with a fatal outcome. There were no differences in the location of the virus and the topography of CNS morphological changes in patients who had died after infection with the Siberian or Far Eastern subtypes of the virus of TBE. The chronic forms of TBE are mainly associated with the Siberian subtype. These three subtypes (European, Far Eastern, and Siberian) may cause the disease via unpasteurized milk.