Reactive oxygen species (ROS) are implicated in spontaneous and xenobiotic-enhanced embryopathies, and protein therapy with exogenous catalase suggests an embryoprotective role, although embryonic catalase activity is only about 5% of adult activity. Using mutant catalase-deficient (acatalasemic, aCat) mice and transgenic mice expressing human catalase (hCat, enhanced catalase activity) compared with a confirmed outbred CD-1 mouse model, we investigated the protective importance of constitutive embryonic catalase against endogenous ROS and the ROS-initiating teratogen phenytoin in embryo culture. Vehicle-exposed aCat and hCat embryos, respectively, exhibited reduced and enhanced catalase activity compared with wild-type (WT) controls, with conversely enhanced and reduced spontaneous embryopathies. Phenytoin was embryopathic in all strains without altering catalase activity but less so in the WT embryos for the aCat and hCat strains, which exhibited about half the catalase activity of CD-1 embryos. Phenytoin, respectively, enhanced and reduced embryopathies in aCat and hCat embryos. Among aCat embryos exposed to phenytoin, embryopathies increased with decreasing catalase activity and were completely blocked by addition of exogenous catalase, which increased embryonic catalase activity to WT levels. These results provide the first direct evidence that (1) the low level of constitutive embryonic catalase protects the conceptus from developmental and xenobiotic-enhanced oxidative stress and (2) embryonic variations in activity of this enzyme affect development.