OBJECTIVE: To explore the mechanism of retinoic acid (RA)　protection　against hyperoxia-induced lung injury. METHODS: Ninety Sprague-Dawley rats were randomly assigned into three groups (n=30 each): air control group (exposed to air) and hyperoxia groups (exposed to 85% oxygen) with and without RA treatment. The RA-treated hyperoxia group received an intraperitoneal injection of RA (500 μg/kg) daily. Lungs were removed by tnoracotomy 4, 7 and 14 days after exposure. Radical alveolar counts (RAC) were observed by hematoxylin and eosin staining under a light microscope. The mRNA level of CTGF in lungs was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The expression of CTGF protein in lungs was detected by immunohistochemistry. RESULTS: With the prolonged hyperoxia exposure, the lungs developed inflammatory cell infiltration, alveolar structure disorders, a decrease in the number of alveoli, and alveolar interstitial thickening in the hyperoxia groups with and without RA treatment. Pathological changes in the RA-treated hyperoxia group were less severe than the untreated hyperoxia group. The CTGF mRNA and protein expression were up-regulated in the hyperoxia groups with and without RA treatment 7 and 14 days after exposure compared with the air control group. Significantly decreased CTGF mRNA and protein expression were noted in the RA-treated hyperoxia group compared with the untreated hyperoxia group 14 days after exposure. CONCLUSIONS: The expression of CTGF mRNA and protein increases in neonatal rats with hyperoxia-induced lung injury. RA may provide protections against the lung injury possibly through down-regulating CTGF expression.