Problem: We have previously shown that human seminal plasma contains immunomodulatory soluble HLA-G (sHLA-G). We investigated whether sHLA-G levels in seminal plasma are associated with a specific 14 base pair (bp) insertion/deletion (ins/del) polymorphism in the 3-untranslated region of the HLA-G gene and/or with the outcome of assisted reproduction treatments (ART) in couples attending a fertility clinic. Method of Study: In a total of 54 unselected couples, sHLA-G levels were measured in seminal plasma samples and blood samples, HLA-G genotyping was performed, and clinical data were collected. Results: The concentration of sHLA-G in seminal plasma samples was significantly associated with the HLA-G 14 bp ins/del genotype of the men; the del14 bp/del14 bp genotype showed the highest level of sHLA-G, and the ins14 bp/ins14 bp genotype showed the lowest level (P = 0.003). We observed a trend for higher seminal plasma levels of sHLA-G/total protein and total sHLA-G in cases with reduced semen quality, where the female partner became pregnant after ART, compared with those couples in which no pregnancy was achieved. Conclusion: These first results are in accordance with a possible role of seminal sHLA-G as an immunomodulatory factor in the female reproductive tract before and at the time of conception.