Background: The expression of human leukocyte antigen (HLA)-G was studied in certain malignancies and its role in escaping from immunosurveillance in cancers was proposed since HLA-G is a non-conventional HLA class I molecule that protects the fetus from immunorecognition during pregnancy. Some particles involved in the regulation of an immune system might represent prognostic value for B-cell chronic lymphocytic leukemia (B-CLL). The identification of novel prognostic factors in B-CLL may help define patient subgroups that may benefit from early therapeutic intervention. Objective: To evaluate the prognostic significance of HLA-G expression in B-CLL patients and its relationship with other well-established prognostic markers. Methodology: Thirty B-CLL patients diagnosed by clinical, morphological and immunophenotyping criteria were studied for HLA-G expression by flow cytometry. The relationship between HLA-G expression and some known prognostic markers was evaluated. Results: HLA-G was expressed in 36.7% of CLL patients at diagnosis, with a mean expression level of 35.31 ± 12.35%. A significant association between HLA-G expression and common prognostic markers of progressive disease was detected. The group of patients with positive HLA-G expression showed significantly higher absolute lymphocyte counts and serum levels of LDH and β2-microglobulin, lower platelet counts, positive CD38 expression and advanced stages of Binet clinical staging. Conclusion: The present study demonstrated that HLA-G expression correlates with prognostic markers of a poor B-CLL outcome, mainly Binet clinical staging and CD38 expression by B-CLL cells, which indicates that this parameter may play a role as an important prognosticator of disease progression and consequently targeted therapy in B-CLL.