The unique human leukocyte antigen (HLA) expression profile of the low polymorphic HLA class Ib molecules HLA-E, HLA-F and HLA-G and the HLA class Ia molecule HLA-C by the extra-villous trophoblast at the feto-maternal interface is well described. These HLA molecules interact with specific receptors on maternal uterine immune cells. The HLA class Ib molecules bind to different receptors such as immunoglobulin-like transcript 2 (ILT2), ILT4 and a number of killer cell immunoglobulin-like receptors (KIRs). Regarding HLA-E and HLA-G, studies indicate that this interaction may stimulate and facilitate placentation by secretion of growth factors, cytokines and angiogenic factors. However, very little is known regarding the functionality of HLA-F. In recent studies, we have focused on a role for HLA-F and HLA-G in the endometrium in relation to embryo implantation and pregnancy success. Endometrial HLA-F expression seems to fluctuate during the menstrual cycle with high levels in mid-secretory endometrium. We have shown that HLA-F protein is expressed by stromal cells and soluble HLA-G by the glands in the endometrium, and correlations with uterine NK and macrophage cell abundance exist. These can be different between women with female infertility experiencing recurrent implantation failure (RIF) and control women attending in vitro fertilization (IVF) for the first time. Furthermore, we have shown that specific HLA-F and HLA-G genotypes, including a single nucleotide polymorphism (SNP) in a progesterone-responsive element, are associated with time-to-pregnancy, measured as number of fertility treatment cycles, in a cohort of couples attending assisted reproductive technology (ART). Finally, the expression levels of endometrial HLA-F protein are associated with the women’s HLA-F SNP genotypes and diplotypes. Our findings support a possible novel role of HLA-F and soluble HLA-G at the implantation site in the endometrium and in the decidua in relation to early pregnancy and pregnancy success.