Objective To investigate the diagnosis and prognosis value of serum S100B protein and neuron-specific enolase (NSE) of hypoxic-ischemic encephalopathy (HIE). Methods A total of 65 cases of HIE children were divided into three groups according to the severity of the patient's condition:mild HIE group (n=22),moderate HIE group (n=24),severe HIE group (n=19);Correspondingly,27 cases of normal full-term newborns at the same period were selected as control group.Electrochemiluminescence immunoassay,ELISA method were applied to dynamically detect the serum NSE,S100B protein levels of the four groups while the NBNA score between each groups was compared,and the correlations among the serum NSE,S100B protein levels and NBNA score were studied as well. Results The serum S100B protein,NSE levels of each HIE group were significantly higher than those of control group (P<0.05),while the NBNA scores were significantly lower than those of control group (P<0.05),and they significantly increased or decreased according to the degree of illness aggravating (P<0.05);The serum S100B protein and NSE levels of HIE children were negatively correlated with the NBNA score (P<0.05),whereas the serum S100B protein and NSE levels were positively correlated (P<0.05);Along with the illness degree aggravating,serum S100B protein,NSE levels of HIE children significantly increased (P<0.05),besides,with extension of the time,the serum S100B protein and NSE levels reduced significantly (P<0.05). Conclusion Dynamic monitoring of serum S100B protein and NSE level has important clinical evaluation value for early diagnosis,judgment of illness degree and treatment effectiveness of neonatal HIE.