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sHLA-G is significantly increased in patients with EC.sHLA-G is highly increased in early stages and in high grade EC.HLA-G5 are more represented than sHLA-G1 molecules in patients with EC.sHLA-G are represented majorly in monomeric forms.sHLA-G dimeric forms are specifically associated to early stages of EC.Human Leukocyte Antigen-G (HLA-G) is known as an immune suppressive molecule; it interacts with several immune cells and inhibits their functions. HLA-G molecule is highly represented in pathological conditions including malignant transformation. To the best of our knowledge this is the first study that focuses on the expression of soluble HLA-G (sHLA-G) in endometrial cancer (EC). We aimed at exploring sHLA-G plasma levels and its prognostic value in EC.We examined total sHLA-G expression as well as the sHLA-G1 and HLA-G5 isoforms expression in plasma samples from 40 patients with EC and 45 healthy controls by a specific sandwich ELISA. Immunoprecipitation and Coomassie blue staining were performed to explore the presence of plasmatic sHLA-G monomers and dimers.sHLA-G plasma level was significantly enhanced in patients with EC compared to healthy controls (p=0.028). Additionally, HLA-G5 molecules were highly represented than sHLA-G1 molecules in EC, at the borderline of significance (p=0.061). Interestingly, sHLA-G has been shown to be increased in early stages (Stages I and II) as well as in high grade EC (Grade 3) that is associated with rapid spread of the disease (p=0.057). sHLA-G positive EC plasma were majorly in monomeric form (75%). Clinically, all the HLA-G dimers were detected in early stages and in high grade of EC.Our data strengthen the implication of HLA-G molecules in EC etiology and especially in progression.