This work investigates the possibility that HLA-G, a molecule modulating innate and adaptive immunity, is part of an immune escape strategy of chronic lymphocytic leukemia cells. A 14 base pair insertion/deletion polymorphism (rs66554220) in the 3'-untranslated region of HLA-G influences mRNA stability and protein expression. The analysis of a cohort of CLL patients confirms that del/del individuals are characterized by higher levels of surface and soluble HLA-G than those of the other two genotypes. In line with its role in immunomodulation, the percentage of regulatory T lymphocytes is higher in del/del patients than in patients with the other genotypes and correlates with the amounts of surface or soluble HLA-G. Furthermore, addition of sHLA-G-rich plasma from CLL patients induces NK cell apoptosis and impairs NK cell lysis, with effects proportional to the amount of soluble HLA-G added. Lastly, the presence of HLA-G 14 bp polymorphism is of prognostic value, with del/del patients showing reduced overall survival, as compared to the other genotypes. These results suggest that i) the HLA-G 14 bp polymorphism influences the levels of surface and soluble HLA-G expression, and that ii) the over-expression of HLA-G molecules contributes to create tolerogenic conditions.