Neurons in the hypothalamus of estrogen receptor alpha-knockout (ER alpha KO) mice have been shown to concentrate radiolabeled estrogen and estrogen treatment regulates the expression of progesterone receptor mRNA. The purpose of the present study was to utilize in situ hybridization histochemistry to determine the anatomical distribution of ERP mRNA in ER alpha KO mouse forebrain. The results of these studies revealed an extensive distribution of ERP mRNA in the hypothalamic regions including medial preoptic area, suprachiasmatic nucleus, paraventricular nucleus, dorsomedial nucleus, medial tuberal nucleus, and the premammillary nuclei. Additional labeled perikarya were also detected in the glomerular layer of the olfactory bulb; tenia tecta; anterior septum; bed nucleus of the stria terminalis; medial, basolateral and cortical nuclei of the amygdala; cerebral and entorhinal cortex; the septohippocampal nucleus; Ammon's horn of the hippocampus and the dorsal raphe. The results of these in situ hybridization histochemical studies have provided novel information about the distribution of ERP mRNA in the ER alpha KO mouse forebrain. In addition, these morphological data provides evidence that estrogen may exert its actions in the ER alpha KO mouse brain via ERP and thereby maintain organizational and activational effects.