One of the most important, robust and evolutionarily conserved functions for neural estrogen receptor (ER) is as a mediator of female sexual behavior. Using homozygotic ER knockout (ERKO) mice we tested the hypothesis that ER controls female receptivity. Females with either two normal copies of the ER gene (wild-types), or an insertational disruption (knockouts) of the ER were ovariectomized. Each female was treated with 17 beta-estradiol (EB) alone, and with EB in combination with progesterone, prior to tests for behavioral receptivity. Under both hormonal conditions female ERKO mice did not display sexual receptivity whereas wild-type litter-mates were receptive to males. Male behavior indicated that females of both genotypes were equally attractive. Brain tissues were examined with immunocytochemical methods showed that ERKOs had greatly reduced levels of ER immunoreactivity in hypothalamus. In sum, the data show that ER is required for the display of sexual receptivity, but is not essential for female attractivity.