Variation in female reproductive traits， such as fertility， fecundity， and fecundability， are heritable in humans， but identifying and functionally characterizing genetic variants associated with these traits have been challenging. Here， we explore the functional significance and evolutionary history of a G/A polymorphism at SNP rs2523393， which is an eQTL for HLA-F and is significantly associated with fecundability (the probability of being pregnant within a single menstrual cycle). We replicated the association between the rs2523393 genotype and HLA-F expression by using GTEx data and demonstrate that HLA-F is upregulated in the endometrium during the window of implantation and by progesterone in decidual stromal cells. Next， we show that the rs2523393 A allele creates a GATA2 binding site in a progesterone-responsive distal enhancer that loops to the HLA-F promoter. Remarkably， we found that the A allele is derived in the human lineage and that the G/A polymorphism arose before the divergence of modern and archaic humans and segregates at intermediate to high frequencies across human populations. Remarkably， the derived A allele is has also been identified in a GWAS as a risk allele for multiple sclerosis. These data suggest that the polymorphism is maintained by antagonistic pleiotropy and a reproduction-health tradeoff in human evolution.