Abstract: Objective To investigate the protective effects of high dose EPO on the brain development of very low birth weight preterm infants in early postnatal period, and to provide reference for clinical practice. Methods Sixty very low-weight preterm infants from the Department of Neonatology, Wenzhou Central Hospital were selected from January 2017 to November 2017, who were randomly divided into treatment group and control group. The treatment group received 1 000 U/kg rhu-EPO once a day for 3 days, the control group was not given rhu-EPO treatment, and the routine treatment of other premature infants was the same as that of the treatment group. The neonatal neurological behavior was measured at 40 weeks of corrected gestational age, the neurological function was evaluated with Gesell scale at 6 months and 12 months of corrected gestational age, and ABR was examined at 40 weeks, 6 months and 12 months of corrected gestational age. Results The blood transfusion rate of the treatment group was lower than that of the control group(43.33% vs. 70.00%), and the difference was statistically significant(χ²=4.343, P=0.037). The NBNA score of the treatment group was better than that of the control group(35.6±2.1 vs. 34.3±1.9) when the gestational age was 40 weeks(P=0.017). The Gesell scale assessment showed that the treatment group was superior to the control group in the large exercise(68.7±4.3 vs. 66.5±3.6) and adaptability(63.8±5.3 vs. 61.2±4.3) at 6 months of corrected gestational age(P=0.036, 0.041). The treatment group was superior to the control group in terms of large exercise(103.1±5.9 vs. 99.1±4.7), fine motor(101.5±5.1 vs. 98.6±5.3), and language(98.4±5.3 vs. 96.1±3.2)(P=0.005, 0.035, 0.046) at 12 months of corrected gestational age. Conclusion Early use of high-dose EPO is beneficial for very low birth weight premature infants and can improve the prognosis of brain development.