The main specific functions of B-cells are carried out with the help of membrane receptors. Binding of the receptor to its ligand activates a cascade of reactions leading to the formation of memory cells and protective antibodies. The study was conducted to analyze the phenotypic profile of sheep blood B-cells in the process of postvaccination immune response to an inactivated vaccine against pathogens of acute intestinal diseases of animals. Romanov sheep at the age of 1.5 years were immunized twice with a 2-week interval. Studies were conducted before vaccination and on the seventh, 14th, and 21 days of the immune response. The phenotype of B-cells was determined by immunoperoxidase staining using monoclonal antibodies to CD receptors. A simple radial immunodiffusion reaction was used to assess IgG levels. Vaccination of sheep with an inactivated vaccine caused an increase in the level of the general population of leukocytes and a subpopulation of B2 cells ( p < 0.05). The absolute number of leukocytes increased on the seventh and 14th days of the primary immune response and on the seventh day of the secondary immune response compared to the initial values. The number of B2 lymphocytes with the CD5 – IgM + phenotype increased and amounted to 9.0 × 10 6 cells/mL on day 7 and 11.2 × 10 6 cells/mL on day 14 of the primary immune response (4.5 × 10 6 cells/mL before the introduction of the vaccine). An increase in the level of the CD5 – CD19 + IgM + CD20 + lymphocyte subpopulation was noted in the first 2 weeks of the immune response and was 2.5 times higher than the initial value. Data were obtained on the absence of the effect of vaccination on the level of lymphocytes with the CD5 + CD19 + IgM + phenotype (B1-cells), which did not change during either the primary or secondary immune response, which indicates the independence of priming of the two main subpopulations of B-cells. The structural components of the immune system in the process of immunogenesis are not activated simultaneously, and when evaluating the effectiveness of vaccination, functional interrelations of immunological indicators are of particular importance. A strong correlation between the indicators of B2‑cells and the level of total immunoglobulins of class G ( r = 0.9) indicates a positive effect of vaccination.