PURPOSE: Vitamin A has been introduced recently for its feasible effect in curing diaphragmatic defect and accelerating lung development during the perinatal period of experimental rats or humans suffering from congenital diaphragmatic hernia (CDH). Despite continual research attention since the fifties to elucidate the influence and mechanisms of vitamin A on pulmonary growth, many presumptive hypotheses remain, along with an inherently high mortality. So we wondered whether prenatal vitamin A alone or combined with dexamethasone could accomplish better results than dexamethasone against the diaphragmatic defect or lung hypoplasia in neonatal rats. METHODS: Pregnant Sprague-Dawley rats exposed to Nitrofen were classified into 5 groups according to the different treatment options. Studies were performd in 2 phases. In study 1, the 24-hour survival rate and preliminary results were observed. In study 2, the incidence and site of CDH, lung/body weight ratio (L/BWR), radial saccular counts (RSC) and maturation of alveolar sac in 3 histomorphologic grades were evaluated among the 5 groups. RESULTS: Vitamin A treated neonatal rats (group III) showed improved lung development compared with rats without treatments (group II) in 24-hour survival rate, L/BWR and alveolar maturation (P<0.001), leading to lung development that was comparable in every aspect to that of the dexamethasone treated rats (group IV). Combined treatment by vitamin A and dexamethasone (group V) improved the incidence of CDH, L/BWR (P<0.001), RSC (P<0.05) and alveolar maturation (P<0.001) when compared with rats treated alone by vitamin A (group III) or dexamethasone (group IV), leading to a level of development that was closest to that of the normal control lungs (group I). CONCLUSION: Vitamin A had a therapeutic effect on pulmonary hypoplasia in the experimental rats, and when combined with dexamethasone it accomplished a better outcome in the treatment of CDH itself or pulmonary hypoplasia. After the problem of vitamin A toxicity is settled, the future of vitamin A as a prenatal therapeutic agent for CDH might gain in appeal.