Objective To investigate the clinical diagnostic value of routine electroencephalogram(EEG)combined with serum miR-146a and miR-129-5p levels in drug-resistant epilepsy.Methods Sixty patients with refractory epilepsy admitted to our hospital from June 2021 to June 2023 were included in the refractory epilepsy group,and 40 healthy volunteers were included in the control group.Human microvascular endothelial drug-resistant cells(HBMECs)continuously exposed to PHT2 were cultured in vitro and transfected with miR-NC(the miR-NC group),miR-146a mimics(the miR-146a mimics group)and miR-129-5p mimics(the miR-129-5p mimics group),respectively.Western blod assay was used to detect the expression of high-mobility group protein B1(HMGB1)in each group.Serum miR-146a and miR-129-5p levels were detected by fluorescent quantitative PCR(polymerase chain reaction),and serum HMGB1 protein expression was detected by Western blod assay.The sensitivity,specificity and accuracy of routine EEG,serum miR-146a and miR-129-5p levels and combined diagnosis of drug-resistant epilepsy were evaluated using the comprehensive consultation results of several expert physicians as the gold standard,and ROC curves were drawn.Results Compared with the control group,the expression of HMGB1 was significantly decreased in the drug-resistant group.Compared with the miR-NC group,HMGB1 expression was significantly decreased in the miR-129-5p mimics group and the miR-146a mimics group(P＜0.05).Compared with the healthy group,the serum HMGB1 protein expression was down-regulated and miR-146a and miR-129-5p expression levels were significantly up-regulated in the refractory epilepsy group.ROC curve analysis indicated that the area under the curve,sensitivity,specificity and accuracy of conventional EEG combined with serum miR-146a and miR-129-5p levels were higher in the diagnosis of refractory epilepsy than that of single diagnostic method.Conclusion The combination of routine EEG and serum miR-129-5p and miR-146a levels can provide help for the diagnosis of drug-resistant patients.