Giant endopolyploid nuclei (>16n) can spontaneously fragment by endomitosis (nuclear internal division) into near-diploid cells with reproductive capacity (depolyploidization), and endotetra/octopolyploidy can undergo chromosome-visible meiotic-like genome reductional divisions also to replicative subcells. These unconventional divisions are associated with production of aneuploidy, which led to the question in this study of whether endopolyploidy, in general, can contribute genetic variability to tumorigenic potential. For this purpose, non-proliferative endopolyploid cells (range: 4n–32n) in near-senescence of normal diploid cell strains were analysed for nuclear–morphogenic changes associated with the presence of diploid-sized nuclei in the cytoplasm. A one-by-one nuclear-cutoff process gave rise to reproducing genome-reduced cells. It was concluded that these unconventional cell divisions are, indeed, suspects of originating genetic variability. Details of these irregular mitoses were compared to ‘mitotic–meiosis’ in primitive organisms, which suggested activation of an ancestral trait in the mammalian cells.