Efficacy and safety of sodium valproate (SV) and lamotrigine (LTG) in treating refractory epilepsy (RE) in children and the predictive value of serum neuron-specific enolase (NSE) and central nervous system specific S100β protein (S100β) on efficacy assessment were explored. A total of 110 RE children admitted to Xuzhou Children's Hospital, Xuzhou Medical University were enrolled. Patients treated with SV alone served as the control group (n=51), and those treated with SV plus LTG as the study group (n=59). Serum NSE and S100β expression levels were measured by enzyme-linked immunosorbent assay (ELISA). The efficacy, seizure frequency, adverse reactions, concentration of serum brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF), and expression of serum NSE and S100β were observed and compared. The total effective rate in the study group was significantly higher than that in the control group, and the seizure frequency and incidence of adverse reactions were significantly lower than that in the control group. The study group showed remarkably higher BDNF and NGF than the control group after treatment. The expression of serum NSE and S100β in effectively treated children were significantly lower than that in ineffectively treated children. The area under the curve (AUC) of serum NSE and S100β were 0.828 and 0.814 respectively. SV combined with LTG is better and safer than SV alone in the treatment of RE in children. Serum NSE and S100β are of high value in predicting the efficacy.