It has been previously demonstrated that the exposure of the liver to estradiol-17 beta (E2) is sufficient to produce cell multiplication in the oviduct of the quail. In this report we determine whether this can also be observed in the rat. Ovariectomized, primed, adult rats were infused over a 3-h period with 2 micrograms E2/kg BW via the jugular vein (systemically). Mitotic figures arrested by colchicine appeared in the uterine luminal epithelium 16-20 h later and remained at maximal levels for the subsequent 3 intervals of 4 h. The minimum dose required to induce a mitotic response was 1.25 micrograms E2/kg BW. There was no increase in response with larger doses. Plasma E2 levels increased linearly with the dose infused systemically. Under the same conditions, E2 infused via the spleen produced mitoses with a similar time course and dose response. However, the amplitude of the response and the plasma E2 levels were significantly depressed. To circumvent problems involved with the interpretation of the results obtained by splenic infusions, we infused 2 micrograms E2/kg BW via the superior mesenteric vein (hepatoportal system). There was no mitotic response and the plasma E2 levels were not elevated above controls. We conclude that a strictly liver mediated, indirect mechanism for the regulation of cell multiplication proposed for quail, is not operative in the rat. In an initial attempt to explain this difference between species, we injected 5 micrograms E2/kg BW sc into hypophysectomized rats. Hypophysectomy had no effect upon the proliferation of the uterine luminal epithelial cells.