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Chromosome missegregation in germ cells is an important cause of unexplained infertility, miscarriages, and congenital birth defects in humans. However, the molecular defects that lead to production of aneuploid gametes are largely unknown. Cdc20, the activating subunit of the anaphase-promoting complex/cyclosome (APC/C), initiates sister-chromatid separation by ordering the destruction of two key anaphase inhibitors, cyclin B1 and securin, at the transition from metaphase to anaphase. The physiological significance and full repertoire of functions of mammalian Cdc20 are unclear at present, mainly because of the essential nature of this protein in cell cycle progression. To bypass this problem we generated hypomorphic mice that express low amounts of Cdc20. These mice are healthy and have a normal lifespan, but females produce either no or very few offspring, despite normal folliculogenesis and fertilization rates. When mated with wild-type males, hypomorphic females yield nearly normal numbers of fertilized eggs, but as these embryos develop, they become malformed and rarely reach the blastocyst stage. In exploring the underlying mechanism, we uncover that the vast majority of these embryos have abnormal chromosome numbers, primarily due to chromosome lagging and chromosome misalignment during meiosis I in the oocyte. Furthermore, cyclin B1, cyclin A2, and securin are inefficiently degraded in metaphase I; and anaphase I onset is markedly delayed. These results demonstrate that the physiologically effective threshold level of Cdc20 is high for female meiosis I and identify Cdc20 hypomorphism as a mechanism for chromosome missegregation and formation of aneuploid gametes., Author Summary Aneuploidy, an abnormal number of chromosomes, is a common defect in sperm and egg cells that is responsible for human infertility, miscarriage, and congenital birth defects. Although these developmental outcomes are prevalent in human reproduction, little is known about the molecular defects that may cause aneuploidy in germ cells. In this study, we identify Cdc20, a critical activator of the APC/C E3 ubiquitin ligase that initiates sister chromosome separation by ordering the destruction of cyclin B1 and securin, as a female infertility gene. We show that female mice with low amounts of Cdc20 have normal fitness but almost exclusively produce aneuploid embryos that fail to thrive and die early in development. The aneuploidy primarily results from chromosome segregation errors in primary oocytes that may be caused by inefficient APC/C-mediated destruction of mitotic cyclins and securin during metaphase I. Thus, our studies reveal that primary oocytes are highly dependent on Cdc20 for accurate chromosome segregation and raise the possibility that Cdc20 insufficiency may be a cause of infertility in otherwise healthy women.