Hormonal status can influence diverse metabolic pathways. Small heterodimer partner (SHP) is an orphan nuclear receptor that can modulate the activity of several transcription factors. Estrogens are here shown to directly induce expression of the SHP in the mouse and rat liver and in human HepG2 cells. SHP is rapidly induced within 2 h following treatment of mice with ethynylestradiol (EE) or the estrogen receptor alpha (ERalpha)-selective compound propyl pyrazole triol (PPT). SHP induction by these estrogens is completely absent in ERalphaKO mice. Mutation of the human SHP promoter defined HNF-3, HNF-4, GATA, and AP-1 sites as important for basal activity, whereas EE induction required two distinct elements located between -309 and -267. One of these elements contains an estrogen response element half-site that bound purified ERalpha, and ERalpha with a mutated DNA binding domain was unable to stimulate SHP promoter activity. This ERalpha binding site overlaps the known farnesoid X receptor (FXR) binding site in the SHP promoter, and the combination of EE plus FXR agonists did not produce an additive induction of SHP expression in mice. Surprisingly, induction of SHP by EE did not inhibit expression of the known SHP target genes cholesterol 7alpha-hydroxylase (CYP7A1) or sterol 12alpha-hydroxylase (CYP8B1). However, the direct regulation of SHP expression may provide a basis for some of the numerous biological effects of estrogens.