OBJECTIVE: Animal trials have demonstrated that memantine has neuroprotective effects on hypoxic-ischemic (HI) brain damage. Whether memantine can improve the long-term prognosis of rats with HI brain damage has not been reported. This study was designed to investigate the long-term effect of memantine therapy on neonatal rats with HI brain damage. METHODS: Sixty postnatal 7-day-old newborn rats were randomly assigned into Normal control, HI and Memantine-treated groups. Memantine (20 mg/kg) was administered immediately after HI in the Memantine-treated group. All subjects received a 5-day training of Morris water maze test from 23 days old. The escape latency (EL) was recorded at 28 and 35 days old. RESULTS: The EL values of the Normal control, HI and Memantine-treated groups at 28 days old were 23.1±21.8, 35.1±5.3, and 20.6±3.4 seconds, respectively. There was a significant difference in the EL value between the HI and the Normal control groups (P<0.05). The EL value of the Normal control, HI and Memantine-treated groups at 35 days old were 19.7±16.7, 35.6±32.3, and 16.3±13.2 seconds, respectively. A prolonged EL induced by HI still existed (P<0.05 vs Normal controls) but memantine treatment shortened the EL (P<0.01 vs HI group) at 35 days old. CONCLUSIONS: Administering memantine immediately after HI can markedly increase the abilities of spatial discrimination, learning and memory and improve the long-term prognosis in rats with HI brain damage.