Elimination of the hepatitis C virus (HCV) due to direct antiviral drug (DAD) action affects alteration in virus phenotype and, accordingly, NK cell functional activity. However, the published data are very contradictory. The aim of the study was to investigae alterations in NK cell subset phenotype after DAD treatment of HCV genotype-dependent chronic viral hepatitis C (CVHC) patients. Materials and methods. 111 CVHC patients and 21 healthy volunteers were examined. The diagnosis was established on epidemiological, clinical and laboratory data. All 111 subjects with CVHC received direct antiviral drugs Sofosbuvir and Velpatasvir for 12 weeks. The study of the NK cell phenotypes wwas analyzed by multicolor flow cytometry. Results. A decreased count of cytokine-producing along with increased frequency of cytotoxic NK cells were found in CVHC patients blood samples with various HCV genotypes prior to DAD treatment. The imbalance of cytotoxic cells with a high level of functional activity was also found in CVHC patients regardless of HCV genotype. The patients with HCV genotypes 1 and 3 showed significantly increased level of immunoregulatory NK cells. In addition, increased count of glycohydrolase (CD38) and ecto-5'-nucleotidase (CD73)-expressing NK cells were found in patients with HCV genotypes 1 and 3. Hence, such alterations in NK cell phenotype in CVHC patients were presented as sustained high viral load which peaking at carriers of HCV genotype 1 that was minimal in patients with HCV genotype 2. The most prominent change in NK cells after DAD treatment was found in CVHC patients with HCV genotype 2 (normalization of CD8-expressing NK cell subset composition and count). Only patients with HCV genotype 2 after treatment had increased frequencies of peripheral blood double-negative CD38–CD73– NK cells. Patients with HCV genotypes 1 and 3 also showed minimally improved in NK cell subset composition after DAD treatment. Conclusion. Evaluation of specific changes in NK cell phenotype during DAD treatment of CVHC patients driven by HCV genotype undoubtedly is of importance and high relevance. The results obtained are novel and complement the insights into CVHC immunopathogenesis. Analysis of NK cell phenotypes and functional activity in patients with CVHC may promote development of new methods for treating HCV infection.