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Soluble HLA‐G (sHLA‐G) levels in human seminal plasma (SP) can be diverse and may affect the establishment of maternal‐fetal tolerance and thereby the outcome of pregnancy. We investigated whether sHLA‐G levels in SP are associated with polymorphisms in the 3′‐untranslated region (UTR) and UTR haplotypes of the  HLA‐G  gene. Furthermore, we compared the  HLA‐G  genotype distribution and sHLA‐G levels between men, whose partner experienced unexplained recurrent miscarriage (RM), and controls. Soluble HLA‐G levels (n = 156) and  HLA‐G  genotyping (n = 176) were determined in SP samples. The concentration of sHLA‐G was significantly associated with several single‐nucleotide polymorphisms (SNPs): the 14 base pair (bp) insertion/deletion (indel), +3010, +3142, +3187, +3196, and + 3509. High levels of sHLA‐G were associated with UTR‐1 and low levels with UTR‐2, UTR‐4, and UTR‐7 ( P  < .0001).  HLA‐G  genotype distribution and sHLA‐G levels in SP were not significantly different between the RM group (n = 44) and controls (n = 31). In conclusion, seminal sHLA‐G levels are associated with both singular SNPs and 3UTR haplotypes.  HLA‐G  genotype and sHLA‐G levels in SP are not different between men whose partner experienced RM and controls, indicating that miscarriages are not solely the result of low sHLA‐G levels in SP. Instead, it is more likely that these miscarriages are the result of a multifactorial immunologic mechanism, whereby the  HLA‐G  3′UTR 14 bp ins/ins genotype plays a role in a proportion of the cases. Future studies should look into the functions of sHLA‐G in SP and the consequences of low or high levels on the chance to conceive.

Soluble HLA‐G levels in seminal plasma are associated with HLA‐G 3′UTR genotypes and haplotypes