Interspecific hybridization between closely related species is commonly associated with decreased fertility or viability of F1 hybrids. Thus, in mouse interspecific hybrids, several different hybrid sterility genes that impair gametogenesis of the male hybrids have been described. We describe a novel effect in hybrids between different mouse species that manifests itself in abnormal growth of the placenta. Opposite phenotypes, that is, placental hypotrophy versus hypertrophy, are observed in reciprocal crosses and backcrosses. The severity of the phenotype, which is mainly caused by abnormal development of the spongiotrophoblast, is influenced by the sex of the conceptus. In general, placental hypertrophy is associated with increased fetal growth. Hypotrophy of the placenta frequently leads to growth impairment or death of the fetus. One of the major genetic determinants of placental growth maps to the proximal part of the mouse X chromosome.