OBJECTIVES: Chromosomal aneuploidy arises from errors in chromosome segregation during cell division, and embryonic aneuploidy is a major cause of implantation failure and miscarriage, which is primarily attributed to maternal meiotic errors. However, recent data accumulated from preimplantation genetic testing have suggested that chromosome segregation errors may also frequently occur during mitotic divisions in early embryos. One proposed factor for these errors is that the cell size in early embryos is larger than that of somatic cells after cleavage, but the exact mechanisms remain unclear. METHODS: To determine the effect of cell size on the incidence of aneuploidy, we established a cultured cell model in which the cell size was artificially enlarged. This model harbored a chromosome carrying the GFP gene, and disappearance of GFP fluorescence served as a quantitative marker for aneuploidy events. By overexpressing genes that increase cell size, we measured the cell size and frequency of aneuploidy using flow cytometry. RESULTS: We observed a significant increase (p=3.67×10-9) in the incidence of aneuploidy in large cells, which supports the hypothesis that a large cell size characteristic of early embryos contributes to the occurrence of chromosomal segregation errors. CONCLUSIONS: Our finding may partly explain the high prevalence of aneuploid mosaicism in human preimplantation embryos.