Background: The central nervous system damage is one of the most common extra hepatic manifestations of chronic hepatitis C viral (HCV) infection, with the prevalence of up to 50% of the infected cases. Previous studies have identified the main clinical, pathogenetic and neurometabolic features of this pathology, which make it possible to suggest its definite nosological independence. However, the morphological pattern of brain lesions in chronic HCV infection remains virtually unexplored, significantly limiting the possibility of comprehensive pathological diagnosis of the disease. Aim: To study morphological patterns and to identify typical and diagnostically significant pathological signs of brain involvement in chronic HCV infection. Materials and methods: This was a retrospective descriptive cross-sectional study performed with a range of immunohistochemical (IHC) and pathomorphological techniques in the autopsy brain samples from patients who died of chronic HCV infection (40 cases) and those who died without any signs of past mental and infectious disorders (the control group, 15 cases). Results: The сharacteristic morphological signs of HCV-associated brain injury are IHC expression of the NS3 viral marker, an increase in CD68-positive microglial cell count, white brain matter microgliosis, perivascular and diffuse round cell inflammatory infiltration, degeneration and loss of neurons, neurophagy, demyelination, axonal degeneration, perivascular sclerosis, fibrous cell gliosis, small perivascular hemorrhages, focal hemosiderosis and calcification. The parameters of the identified abnormalities differ significantly depending on the brain region (p < 0.001). The identification of the HCV NS3 marker in the nervous tissue has the definitive diagnostic value. Conclusion: The body of histopathological abnormalities found in various parts of the brain from the infected patients represents the morphological equivalent of the clinical and functional manifestations of HCV-associated cerebral dysfunction. The results obtained can be used to improve the pathological diagnostics of brain lesions in chronic HCV infection; their implementation is feasible in routine pathological practice.