Hyperoxia is known to cause cerebral white matter injury in preterm infants with male sex being identified as an independent risk factor for poor neurodevelopmental outcome. We investigated the underlying mechanisms behind such a sex dependent difference by a comaparative protein profiling of male and female murine progenitor oligodendrocytes treated with 3 % or 80% oxygen. We demonstrate that following hyperoxia, the male derived oligodendrocyte progenitor cells (OPCs) are severely affected with respect to their energy metabolism, stress response and especially, maturation as compared to their female counterparts.