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We attempted to demonstrate a relation between a loss of replication control, centromere dysfunction, and predisposition to non-disjunction. Couples with a Down syndrome offspring were the high-risk probands. One-color FISH (fluorescent in-situ hybridization) was applied to interphase nuclei (lymphocytes). Replication pattern of two pairs of alleles, RB-1 and 21q22, were studied, and the rate of aneuploidy was estimated using two alpha-satellite probes of chromosomes 8 and 18. Our results suggest the existence of an association between replication timing and the rate of non-disjunction. A higher rate of allele asynchrony and aneuploidy was found in older women and in mothers of a Down syndrome offspring. These findings may reflect a predisposition for meiotic non-disjunction in these women.