During the preimplantation period, in vitro cultured males have a higher metabolic rate, different gene expression, and grow faster than females. It has been suggested that under some stress conditions male embryos are more vulnerable than females; however, the biological fragility of male embryos is little understood. Since many forms of stress result in the overproduction of cellular reactive oxygen species (ROS), we addressed the hypothesis that the connection between female advantage during early developmental stages and heat stress involves ROS and differential gene expression of G6PD, an X‐linked gene related to oxidative stress. We have found that after compaction, female heat‐stressed embryos have less relative amounts of H₂O₂ than males, and female embryos survive better than males under in vivo or in vitro heat stress situations. In addition, in vitro produced female embryos grow slower than male embryos, have differential mRNA transcription of G6PD and also of some genes situated on autosomal‐chromosomes (Sox, Bax, and Oct‐4). Moreover, by inhibiting G6PD, all differences generated by oxidative stress between male and female embryos disappear. For the first time, we provide an experimental demonstration of a mechanism that explains why following exposure to heat stress‐induced ROS, female preimplantation embryos are more resistant than males. Mol. Reprod. Dev. © 2005 Wiley‐Liss, Inc.