Female mice deficient in steroid 5α-reductase type 1 have a decreased litter size. The average litter in homozygous deficient females is 2.7 pups vs. 8.0 pups in wild type controls. Oogenesis, fertilization, implantation, and placental morphology appear normal in the mutant animals. Fetal loss occurs between gestation days 10.75 and 11.0 ommensurate with a midpregnancy surge in placental androgen production and an induction of 5a-reductase type 1 expression in the decidua of wild type mice. Plasma levels f androstenedione and testosterone are 2- to 3-fold higher on gestation day 9, and estradiol levels are chronically elevated by 2- to 3-fold throughout early and midgestation in the knockout mice. dministration of an estrogen receptor antagonist or inhibitors of aromatase reverse the high rate of fetal death in the mutant mice, and estradiol treatment of wild type pregnant mice causes fetal wastage. The results suggest that in the deficient mice, a failure to 5a-reduce androgens leads to their conversion to estrogens, which in turn causes fetal death n midgestation. These findings indicate that the 5α-reduction of androgens in female animals plays a crucial role in guarding against estrogen toxicity during pregnancy. (Molecular Endocrinology 11: 917–927, 1997)