Chronic lymphocytic leukemia (CLL) is a strikingly heterogeneous disease both at the molecular level and clinical disease course. The key proliferation and survival signals malignant B cells obtain within lymph nodes or bone marrow. Moreover, CLL B cells and tumor microenvironment dynamically co-evolve organizing inflammatory and immunosuppressive microenvironment by direct contact with surrounding cells and secretion of cytokines, growth factors, or extracellular vesicles. Finding a way to weaken obtaining by malignant B cells supportive signals may improve CLL outcome and optimize treatment strategies. The aim of this study was to evaluate whether CD150 and CD180 cell surface receptors could be involved in the regulation of CLL B cells-derived cytokines (CCL3, CCL4, IL-6, and IL-10). The study was performed on malignant B cells isolated from peripheral blood of primary CLL patients. Flow cytometry, qPCR, ELISA, western blot, ex vivo cell surface ligation assay, ex vivo drug sensitivity assay, and cell viability assay were used in this study. The CCL3, CCL4, IL-6, and IL-10 mRNA expression levels were heterogeneously presented among studied CLL cases. The elevated CCL3/CCL4 and decreased IL-6/IL-10 expression level are specific features of CLL B cells with positive CD150 and CD180 expression status. Ligation of CD150 and CD180 receptors did not affect CCL3/CCL4 mRNA expression level in CLL B cells, while IL-6 and IL-10 were significantly decreased. After malignant B cells stimulation via CD150 and CD180 observed reduced IL-10 but not IL-6 level in culture supernatants. Ligation of CD150 and CD180 was linked to the classical NF-κB pathway via regulation of phosphorylation level of NF-κB inhibitor IκBα. We found several correlations between basal mRNA expression levels of CLL3, CCL4, IL-6, and IL-10 in CLL B cells and their sensitivity to chemotherapeutic drugs ex vivo. High CCL3/CCL4 and low IL-10 mRNA expression levels are associated with malignant B cells` sensitivity to BEN, while high IL-6 levels are a sign of CLL B cells` resistance to FC. The revealed involvement of CD150 and CD180 in cytokine regulation expands our knowledge of the role of CD150 and CD180 in the pathobiology of CLL and their contribution to a favorable clinical outcome. Determining the cytokines expression levels together with CD150 and CD180 expression status may help to predict the responsiveness of CLL B cells to chemotherapeutic drugs and optimize personalized chemotherapy scheme.