Aim To investigate the hub genes associated with response to valproate treatment in patients with epilepsy by using weighted gene co-expression network analysis.Methods We downloaded data from the GEO database and constructed the gene co-expression network.Pearson correlation test was used to calculate the correlation between module genes and clinical traits, to screen gene modules significantly associated with response to valproate treatment, and to screen hub genes according to the connectivity within modules.GO functional enrichment analysis and KEGG pathway analysis were used to annotate the functions of the modules.Results A total of 12 gene co-expression modules were constructed from the correlations of gene expression, in which the yellow module was significantly correlated with the drug treatment(r=0.57, P<0.000 1)and the blue module was significantly correlated with the response to valproate(r=-0.53, P<0.000 1).We found that S1PR5, SARM1 and MAGED1, FBXO31 were in the hub of the co-expression network.The biological annotation function revealed that the genes in both modules were mainly enriched in immune response and MPAK pathways.Conclusions Our work delivers preliminary data that valproate treatment causes the changes of immune and metabolic pathways in patients, and the response to epilepsy may be related to the expression of MAGED1, FBXO31.