Placental weight in rats varied inversely with litter size and the level of plasma 17β-estradiol. Administration of estrogen to intact, pregnant “low litter” animals prevented placental hypertrophy only when normal plasma estradiol levels were doubled. In “normal litter” animals estrogen administration had no effect on placental weight in spite of significant increases in plasma estradiol, and progesterone administration also had no effect. Pregnant rats responded to ovariectomy with marked placental hypertrophy when pregnancy was sustained by progesterone substitution therapy; however, above that required to maintain pregnancy the dose of progesterone did not affect the degree of placental response. On the other hand, normal plasma estradiol levels reduced the placental hypertrophic response of ovariectomized animals, and suppression of the response occurred when estradiol levels were doubled. The reduction in plasma progesterone evident in normal pregnant animals between days 19 and 21 also occurred in ovariectomized animals in spite of continuing progesterone substitution therapy, suggesting an extraovarian mechanism involved in progesterone metabolism. (Endocrinology93: 1173, 1973)