© 2015 Wiley Periodicals, Inc.Background: In recent years, the clinical and biological features governing the clinical course of chronic lymphocytic leukemia (CLL) have been most extensively studied. Human leukocyte antigen-G (HLA-G) allows tumor cells to escape from the antitumor effect of the immune system. Recent studies have shown that various tumor cells show an increased HLA-G expression. Data regarding HLA-G expression in CLL are limited and controversial. The aim of this work is to evaluate flow cytometry study of HLA-G expression on cell surface and assess its relationship with other prognostic factors (CD38, ZAP70, beta 2 microglobulin [β2MG]) in patients with CLL. Design and methods: Forty-five newly diagnosed CLL cases. White blood cell count, lymphocyte absolute count, hemoglobin level, platelet count, serum lactate dehydrogenase activity, and serum β2MG level were studied at admission. In each patient, morphologic diagnosis of B-CLL was confirmed by flow cytometry HLA-G, CD38 and ZAP70 expression levels were measured with four-color flow cytometry. Results: HLA-G positivity ranged between 1% and 12% in CLL patients. A significant correlation was found with CD38, ZAP70, disease stage, and β2MG (P < 0.001). The off-treatment follow-up period was longer in the HLA-G negative group (P < 0.022). Conclusions: In conclusion, we suggest that, in addition to other prognostic factors, surface HLA-G expression can be considered as an independent prognostic factor. However, our work should be confirmed by further prospective studies, a longer off-treatment follow-up period, and a standardized method.