In infertile cycles in rats, the corpus luteum (CL) ceases producing progesterone in about 2 days and is eliminated by structural luteolysis. Glucocorticoids disrupt the ovarian cycle and interfere with structural luteolysis. We studied the effects of the glucocorticoid dexamethasone (DEX) on rat luteolysis. Cycling rats were treated during 3 days (from estrus to diestrus) with different doses (0.025, 0.1, 0.4, and 1 mg/rat) of DEX or vehicle. DEX-treated rats showed a necrotic pattern of cell death, affecting exclusively the last generation of regressing CLs. In these animals, selective apoptosis of luteal endothelial cells, detected by both morphological characteristics and TUNEL assay, was observed on the morning of proestrus and was followed by necrosis of the luteal tissue. These effects were dose related. With the lowest DEX doses (0.025 and 0.1 mg), only some of the animals were affected and showed smaller necrotic areas in CLs. The deleterious effects of DEX on endothelial cells were in keeping with the immunohistochemical localization of glucocorticoid receptors in the endothelial cells of the last CL generation. The results of this study strongly suggest that DEX-induced selective apoptosis of endothelial cells leads to ischemic necrosis of the luteal tissue and raises the possibility that actions on endothelial cells may be underlying glucocorticoid-induced effects on the ovary.