We have previously demonstrated placentas from laboring deliveries at high altitude have lower binding of hypoxia-inducible transcription factor (HIF) to DNA than those from low altitude. It has recently been reported that labor causes oxidative stress in placentas, likely due to ischemic hypoxic insult. We hypothesized that placentas of high-altitude residents acquired resistance, in the course of their development, to oxidative stress during labor. Full-thickness placental tissue biopsies were collected from laboring vaginal and nonlaboring cesarean-section term (37-41 wk) deliveries from healthy pregnancies at sea level and at 3,100 m. After freezing in liquid nitrogen within 5 min of delivery, we quantified hydrophilic and lipid metabolites using (31)P and (1)H NMR metabolomics. Metabolic markers of oxidative stress, increased glycolysis, and free amino acids were present in placentas following labor at sea level, but not at 3,100 m. In contrast, at 3,100 m, the placentas were characterized by the presence of concentrations of stored energy potential (phosphocreatine), antioxidants, and low free amino acid concentrations. Placentas from pregnancies at sea level subjected to labor display evidence of oxidative stress. However, laboring placentas at 3,100 m have little or no oxidative stress at the time of delivery, suggesting greater resistance to ischemia-reperfusion. We postulate that hypoxic preconditioning might occur in placentas that develop at high altitude.