Periventricular leukomalacia (PVL) involves free radical injury to developing oligodendrocytes (OLs), resulting from ischemia/reperfusion, particularly between 24 and 32 gestational weeks. Using immunocytochemistry and Western blots, we tested the hypothesis that this vulnerability to free radical toxicity results, in part, from developmental lack of superoxide dismutases (SOD)-1 and -2, catalase, and glutathione peroxidase (GPx) in the telencephalic white matter of the human fetus. During the period of greatest PVL risk and through term (≥37 weeks), expression of both SODs (for conversion of O2− to H2O2) significantly lagged behind that of catalase and GPx (for breakdown of H2O2), which, in contrast, superseded adult levels by 30 gestational weeks. Our data indicate that a developmental “mismatch” in the sequential antioxidant enzyme cascade likely contributes to the vulnerability to free radical toxicity of the immature cerebral white matter, which is “unprepared” for the transition from a hypoxic intrauterine to an oxygen-rich postnatal environment. All enzymes, localized to astrocytes and OLs, had higher-than-adult expression at 2 to 5 postnatal months (peak of myelin sheath synthesis), suggesting an adaptive mechanism to protect against lipid peroxidation during myelin sheath (lipid) synthesis. The previously unrecognized dissociation between the expression of the SODs and that of catalase and GPx in the fetal period has potential implications for future antioxidant therapy in PVL.