Abstract: Objectives　To investigate the effect of rhEPO on newborn rats with necrotizing enterocolitis (NEC). Methods Sixty newborn Sprague-Dewley (SD) rats at the age of 48 hours were randomly divided into 5 groups: control group, NEC group, and intervention groups 1, 2 and 3 treated with rhEPO. The rats were fed rat breast milk substitutes and stressed under hypoxia and cold exposure to establish NEC model. The rats with NEC were treated with different doses of rhEPO (0.1U/ml, 1U/ml and 10U/ml) in intervention groups. The expression of Bcl-2 and caspase-3 were measured by immunohistochemistry, and intestinal pathological changes were observed using HE staining. The value of positive expression was analyzed by IOD (integral optical density) image analysis system. Results Abdominal distention, decreased activity and unresponsiveness occurred in NEC rats 24 hours after stress exposure, and pale skin, decreased skin temperature and respiratory rhythm change were observed in severe cases. The symptoms appeared later and milder in three intervention groups. The NEC incidence of newborn rats was as followings: control group(0%), model group(60%), intervention group 1( 30%), intervention group 2(18.2%), intervention group 3(9.1%) and the difference was significant between each group (P=0.008). The grades of intestinal injury, the expression of active caspase-3 and Bcl-2 were significantly different among groups (P<0.01). Intestinal injury was the most severe and the expression level of active caspase-3 was the highest in NEC group. After rhEPO treatment, the intestinal injury and the production of active caspase-3 protein were decreased, and the expression of Bcl-2 was increased. Conclusions Oral rhEPO could decrease the expression of intestinal active caspase 3, and increase the expression of Bcl-2. The protective effect of rhEPO on NEC is dosedependent.