OBJECTIVE To systematically evaluate the long-term clinical efficacy and safety of mild hypothermia therapy in neonates with hypoxic-ischemic encephalopathy (HIE). METHODS All randomized controlled trials (RCTs) of mild hypothermia therapy for neonatal HIE from inception to March 2014 were retrieved from databases including Cochrane Library, PubMed, Embase, CBMdisc, and Wanfang Data. Meta analysis was performed using RevMan 5.1 Software. RESULTS Eight RCTs met the search criteria. The results of Meta analysis showed that, compared with the control group, systemic hypothermia significantly reduced the mortality rate and the incidence of growth delay (RR=0.73, 95% CI: 0.61-0.89; RR=0.70, 95%CI: 0.54-0.93); selective head or systemic hypothermia therapy significantly reduced the incidence of cerebral palsy (RR=0.65, 95%CI: 0.46-0.94; RR=0.67, 95%CI: 0.52-0.86) up to 12-24 months of age. One study reported that hypothermia reduced the mortality rate and the rate of a composite end point of death or severe disability compared with the control group at 6 to 7 years of age. The incidence of adverse events including sinus bradyarrhythmia, thrombocytopenia and hypoglycemia was significantly higher in the hypothermia group than in the control group, whereas the incidence of cardiac arrhythmia, hypotension, thrombosis or bleeding, hypokalemia, sepsis, and liver dysfunction showed no significant differences between the two groups. CONCLUSIONS Mild hypothermia therapy demonstrates a significant efficacy in children with HIE up to 12-24 months of age, but there is still a need for further research on childhood outcomes after mild hypothermia for neonatal HIE. This therapy has few adverse effects and a high clinical tolerability.