We provide compelling genetic evidence for a role of COUP-TF2 in early human ovary development. We identified three protein-truncating, complete loss-of-function mutations that are acting in a dominant fashion. These findings indicate that NR2F2 may function in a dosage-sensitive manner, which is similar to other gene mutations known to disrupt human sex determination. This indicates that COUP-TF2 may be required to establish ovary identity during early human gonad development by the repression of genes involved in testis determination.