Although studies have established that immune mechanisms are important in controlling tick-borne encephalitis virus (TBEV) infection, the interactions of different TBEV strains with cells of innate and adaptive immunity are not well understood. In this study, the ability of two Far Eastern subtype TBEV strains (Dal'negorsk and Primorye-183) with various degrees of pathogenicity for humans to modulate the expression of membrane molecules differently on human immune cells were investigated using a whole-blood flow cytometry-based assay. The whole-blood samples (from 10 healthy donors) were infected with TBEV strains and analyzed for the virus binding to the blood cells, as well as expression of adhesion (CD11b and ICAM-1) and activation (CD69, CD25, CD95) molecules on the surfaces of monocytes, granulocytes, natural killer (NK) cells, and T-lymphocytes (CD4+, CD8+) at selected times (3, 6, and 24 h post-infection). It was found that the highly pathogenic Dal'negorsk strain penetrated rapidly and was actively replicated in the blood cells, inducing downregulation of CD11b, ICAM-1, and CD69 on monocytes and a significant decrease of NK cells expressing CD69, CD25, CD95, and CD8 T-lymphocytes expressing CD69 compared with the mock-infected cells. The nonpathogenic Primorye-183 strain penetrated slowly and was replicated in the blood cells, but caused a significant increase in the adhesion and activation of molecule expression to trigger innate defense mechanisms and enable the rapid elimination of the virus from the organism. Thus, TBEV-induced activation or suppression of adhesion and activation receptors expression form an essential part of fundamental virus properties, that is, virulence and pathogenicity.