Major reproductive events such as menstruation, ovulation, implantation, and cervical ripening are characterized by an increased number of invading leukocytes in the tissues. Sex steroid hormones, particularly estrogens, play an important role in these dynamic changes in the female reproductive tract. Estrogens have also been implicated in the pathogenesis of many common pathological conditions associated with leukocyte infiltration and immunological dysfunction, such as auto-immune diseases and atherosclerosis. Although the two estrogen receptor (ER) subtypes, ERα and ERβ, have been found in different leukocyte populations in tissues and in peripheral blood, there is still very little known about functional activity and importance of ERs in blood cells. To elucidate the different roles for ERα and ERβ in peripheral blood leukocytes, we used microarray gene expression profiling of rat peripheral blood leukocytes subjected to in vivo treatment with estradiol (E ₂ ), the selective ERα agonist 4,4′,4″-(4-propyl-[1 H ]-pyrazole-1,3,5-triyl) tris phenol (PPT), and the selective ERβ agonist 2,3- bis (4-hydroxyphenyl)-propionitrile (DPN). We report the identification of genes that were commonly regulated by E ₂ , PPT, and DPN, and genes that were regulated either by the ERα or ERβ agonist. Further confirmatory analyses of the selected regulated genes 12-lipoxygenase, fibulin-1, furin, and calgranulin B are also presented. These results were then compared with those from the uterine tissue of the same animals. Our study demonstrates that peripheral blood leukocytes are responsive to estrogens. E ₂ and selective ERα and ERβ agonists regulate a number of genes that may contribute to inflammation and remodeling of the extracellular matrix.