Objective To investigate the effect of erythropoietin (EPO) on the expression of MMP-2 in hippocampus of neonatal rats after hypoxic-ischemic brain damage (HIBD), and the mechanism of its neuroprotective effect. Methods Neonatal Sprague-Dawley rats of 7 days old were randomly divided into three groups (n?=?48 in each group): sham-operated group, HIBD group and EPO treated group, then each group was further divided into four subgroups (n?=?12) based on different time points following the injection of medication ( 6 h, 24 h, 3 d, 7 d). The expression of MMP-2 in hippocampus was determined by immunohistochemistry and real-time lfuorescent quantitative PCR method. Results Immunohistochemistry: MMP-2 has a small amount of expression in the hippocampus of the sham-operated group, and at each time point, there is no statistically signiifcant difference (P?>?0.05);The expression of MMP-2 in HIBD group and EPO group all show a trend of increase, and peaked at 7 d, the differences between each time point in two groups are statistically signiifcant (P??0.05). Gene expression in HIBD group at 24 h and 7 d points showed twin peaks, and the peak is higher at the 7 d point, but without difference (P?>?0.05). MMP-2 expression of EPO group presents a trend of increase, and differences are signiifcant between each time point (P?