Deviations from a Mendelian 1:1 transmission ratio have been observed in human and mouse chromosomes. With few exceptions, the underlying mechanism of the transmission-ratio distortion remains obscure. We tested a hypothesis that grandparental-origin dependent transmission-ratio distortion is related to imprinting and possibly results from the loss of embryos which carry imprinted genes with imprinting marks that have been incorrectly reset. We analyzed transmission of alleles in four regions of the human genome that carry imprinted genes presumably critical for normal embryonic growth and development: 11p15.5 (H19, IGF2, HASH2, etc.), 11p13 (WT1), 7p11-12 (GRB10), and 6q25-q27 (IGF2R), among the offspring of 31 three-generation Centre d'Etude de polymorphism Humain (CEPH) families. Deviations from expected 1:1 ratios were found in the maternal chromosomes for regions 11p15.5, 11p13, and 6q25-27 and in the paternal chromosomes for regions 11p15 and 7p11-p12. The likelihood of the results was assessed empirically to be statistically significant (p = 0.0008), suggesting that the transmission ratios in the imprinted regions significantly deviated from 1:1. We did not find deviations from a 1:1 transmission ratio in imprinted regions that are not crucial for embryo viability (13q14 and 15q11-q13). The analysis of a larger set of 51 families for the 11p15.5 region suggests that there is heterogeneity among the families with regard to the transmission of 11p15.5 alleles. The results of this study are consistent with the hypothesis that grandparental-origin dependent transmission-ratio distortion is related to imprinting and embryo loss.