Keratin 8 (mK8) and its partner keratin 18 (mK18) are the first intermediate filament proteins expressed during mouse embryogenesis. They are found in most extraembryonic and embryonic simple epithelia, including trophectoderm, visceral yolk sac, gastrointestinal tract, lungs, mammary glands, and uterus. We report that a targeted null mutation in the mK8 gene causes mid-gestational lethality. Mutant embryos are growth retarded and suffer from internal bleeding, with an abnormal accumulation of erythrocytes in fetal livers. The mK8- phenotype has 94% penetrance, with a few mice surviving into adulthood. We suggest that mK8/mK18 filaments are important for the integrity of the fetal liver, like specialized human epidermal keratins for the integrity of the epidermis. This phenotype in mice differs from the reported function of simple epithelium keratins in Xenopus at the gastrulation stage. In mice, mK8 fulfills a vital function at 12 days postcoitum.