Significance Several techniques have identified ELF3 as particularly important in regulating trophoblast-specific HLA-C expression. This results from a single-nucleotide difference in the promotor of the HLA-C gene at the RFX5 binding site that creates an ELF3 binding site not found in the HLA-A or HLA-B promoters. We discovered a superenhancer and a positive autoregulatory feedback loop that promotes expression of the ELF3 gene in trophoblasts. Disruption of either the superenhancer by (+)-JQ1 or interference with the positive-feedback loop by wrenchnolol decreased ELF3 levels, and thus HLA-C expression. Aberrations of this complex regulatory system could be involved in control of infection, miscarriage, preterm birth, preeclampsia, as well as parturition in normal pregnancy and in development of choriocarcinoma.