The response of folliculo-stellate (FS) cells of the anterior pituitary to estrogen has been studied in two strains of rat which differ in estrogen responsiveness. Fischer 344 (F344) rats are highly estrogen-responsive in comparison to Sprague-Dawley (S-D) rats. Ovariectomized adults were implanted with silastic capsules containing 17β-estradiol benzoate. Control and experimental animals were sacrificed 10 and 20 days after implantation of the silastic capsules. Most FS cells of F344 rats revealed dramatic changes, i.e. activation as phagocytes, after 10 and 20 days of estrogen treatment. These activated FS cells separated themselves from adjacent parenchymal cells and frequently contained phagosomes which included portions of granulated cells, mostly somatotrophs and lactotrophs. They also contained a variety of lysosomal dense bodies and dilated cisterns of endoplasmic reticulum. Endfeet processes abutting the parenchymal basal lamina contained large aggregates of dumbbell-shaped granules and tubulo-vesicles. Subjacent to the endfeet processes the basal lamina was often discontinuous, and profiles suggesting uptake of fragments of the basal lamina by FS cells were evident. Most FS cells of estrogen-treated S-D rats either were identical to those of controls or were only minimaly modified. However, a few activated FS cells were present and these contained a variety of lysosomal dense bodies and phagosomes, as well as lipid inclusions and dilated endoplasmic reticulum. Endfeet projections at the parenchymal basal lamina contained very few dumbbell-shaped granules or tubulo-vesicles, and the basal lamina was intact. Estrogen sensitivity of F344 rats appears, at least in part, to be associated with activation of FS cells as phagocytes and in degradation of the parenchymal basal lamina. This specific cellular response may thus contribute to, or underlie, the vascular reorganization and angiogenesis which occur during onset stages of estrogen-induced tumors of the anterior pituitary.