Objective: To study the changes of phosphorylated eukaryotic translation initiation factor 2α[eIF2α(p)]and expression of activing transcription factor 4(ATF4) in neonatal rats with hypoxic-ischemic brain damage(HIBD). Methods: Eighty 7-day-old Sprague-Dawley rats were randomly divided into 2 groups:sham operation group(n = 40) and HIBD group(n = 40). HIBD models were established by Rice method. At 6,12,24 and 72 h after hypoxia-ischemia (HI),the brain tissue of rats in HIBD group was obtained to prepare section. The changes of phosphorylation of eIF2α and expression of ATF4 in the lesion side cerebral cortex in rats were detected by immunohistochemical staining. The sham operation group was dealt with the same method without HI. Results: The expression level of eIF2α (p) and ATF4 increased at 6 h after HIBD,peaked at 12 h,decreased significantly at 72 h,but was still higher than that of sham operation group(P < 0.01). The differences in the expression level of eIF2α(p) and ATF4 in HIBD group among different time points were significant(P < 0.01). Conclusion: eIF2α(p) and ATF4 participate in the pathophysiological process of HIBD. HIBD may induce endoplasmic reticulum stress reaction,which initiate PKR-like endoplasmic reticulum kinase(PERK) mediated unfolded-protein response(UPR) signal pathway.