The phenotype of mice with a targeted disruption of the insulin-like growth factor II gene (IGF-II null mice) is growth retardation of both fetus and placenta during the last two thirds of gestation (1). We have compared the placenta of IGF-II null and wild-type mice from days 9-18 of gestation. No morphological differences were detected until after day 12 of gestation, when a new population of placental cells, the glycogen cells, normally first appears. Fewer glycogen cells were present in the null placenta compared to the wild-type placenta on days 13, 15, and 18 of gestation. By day 15, glycogen cells constituted approximately 50% of the basal zone cells in the wild-type placenta, but only 20% of the basal zone cells in the null placenta (P 0.50). The glycogen content of both spongiotrophoblasts and glycogen cells was significantly reduced in the null placenta, suggesting that IGF-II may be an important regulator of glycogen synthesis in the placenta. These results indicate that IGF-II regulates cell number in the placenta and may play an important role in the differentiation of glycogen cells and the production of glycogen by placental cells.