Oocyte selection with the highest competence is a major goal in IVF. Several studies demonstrated that non-classical HLA class I HLA-G molecule modulation creates a tolerogenic microenvironment at the feto-maternal interface and is implicated in embryo implantation. This study investigated if soluble HLA-G molecules producted by the cumulus-oocyte complex (COC) are markers of oocyte maturation. sHLA-G molecule levels were analyzed using Bio-Plex assay in 152 COC supernatants obtained from 42 women and maturated by an 'in vitro maturation procedure'. The presence of sHLA-G molecules was confirmed by Western blotting technique. The results demonstrate detectable amounts of sHLA-G molecules ranging from 300 to 800 pg/ml in 14/73 (19%) COCs that generated mature oocytes and complete absence of detectable sHLA-G antigens in the supernatants of COCs that corresponded to immature oocytes. The detection of sHLA-G molecules in the COC culture supernatants corresponding to matured oocytes is proposed to be a marker to identify gametes with higher functionality. This non-invasive marker could be used, in addition to morphological approaches, to reduce the number of fertilized oocytes and transferred embryos.