OBJECTIVE: To study whether Panax Notoginseng Saponins (PNS) has a protective effect on brain cells in neonates with hypoxic-ischemic encephalopathy (HIE). METHODS: Forty-two neonates with HIE were randomly assigned into the treatment group (n = 24) and the control group (n = 18). Ten normal neonates served as a reference group In addition to conventional therapy, the treatment group received PNS, 12-15 mg/kg daily for 5-8 days. Concentrations of intra-erythrocytic free calcium (RBC [Ca2+ ]i) in the three groups were assayed by a new staining calcium agent Indo-1/Am at the time of admission (before the treatment), and 48 hours and 72 hours after the treatment. RESULTS: Before the treatment, RBC [Ca2+ ]i concentrations in the HIE treatment group and control group were significantly higher than that of the normal non-HIE reference group ( P < 0.01); and there was no obvious difference between the two HIE groups. RBC [Ca ]i concentration in the PNS group obviously decreased at 48 hours and 72 hours after the PNS treatment compared with the control HIE group ( P <0.01). A significant difference was found in the RBC [Ca2+ ]i concentration in the; PNS group before and after the PNS treatment for 72 hours [(2.619 ± 0.175) vs (2.358 ±0.280); P <0.01]. PNS treatment significatly reduced central respiratory failure (20% vs 100%), circulatory dysfunction (33.3% vs 83.3%) and gastrointestinal symptoms (16.7% vs 91.7%) compared to the non-treated HIE group. CONCLUSIONS:Treatment with PNS improves the clinical symptoms in neonates with HIE. The mechanism of this neuro-protective effect may involve the reduction of intra-ery throcyte free calcium overload.