An antibody or antigen-binding fragment thereof which specifically binds the α3 domain of a HLA-G protein, in particular binds the β2-microglobulin free HLA-G protein exhibiting an α3 domain. The nucleic acid molecules encoding a human HLA-G α3 domain polypeptide, which is selected from a group of specific sequences, and vectors for the cloning and/or expression of such nucleic acid molecules, recombined cells or cell lines and compositions for use in a host in need thereof to interfere with and neutralize the immune down-regulation due to HLA-G proteins, and/or improving or treating conditions showing HLA-G+ lesions, and/or improving or treating a neoplasic condition or disease. A method of producing the antibody or antigen-binding fragment thereof, immunogenic compositions for use to elicit in a host an immune response against the α3 domain of HLA-G protein, and an in vitro method for detecting HLA-G protein in a sample are also described.