Objective Shkbp is also called Shkbp1, can competitively inhibit binding CIN85 and c-Cbl, thereby blocking the epidermal growth factor receptor (EGFR) endocytosis and degradation, to play a role in tumor promotion. This study aims to explore the changes in blood cell classification and T cell subsets in blood, bone marrow, and spleen in Shkbp1-deletion (Shkbp-1^-/-) mice. Methods Shkbp-1^-/- transgenic mice were identified by PCR genotyping. Blood cell classification was performed using an automatic classification system. Flow cytometry was used to detect the T lymphocyte subsets in the blood, bone marrow, and spleen of Shkbp-1^-/- and control mice. Results Routine blood examination showed that neutrophils and eosinophils tended to increase and showing significant differences, and there was no significant difference in lymphocytes. The flow cytometry results showed that there was a decrease of CD4⁺CD8⁺double positive cells and increase of bone marrow CD3⁺ and CD4⁺ cells in the control group. However, there was a decreasing trend of CD3⁺, CD4⁺, CD8⁺, and CD4⁺CD8⁺cells in the spleen tissues. Conclusions Shkbp1 is involved in the maturation and differentiation of blood cells, and affects the number of immune cells. This study lays a foundation for the study of how Shkbp1 is involved in the differentiation of blood cells.