Objective To investigate the association of the polymorphisms of the multidrug resistance-associated protein 1 (MRP1) gene-G128C (rs41395947), C218T (rs41494447), G2168A (rs4148356), and G3173A (rs41410450), and serum MRP1 levels with drug resistance in epilepsy, and to further determine which antiepileptic drug (AED) epileptic patients with the polymorphisms tend to be resistant to.Methods A questionnaire was conducted among epileptic patients (31 cases resistant to AEDs and 67 cases sensitive to AEDs) who attended the outpatient department and ward of the First Affiliated Hospital of Baotou Medical College or the Epilepsy Clinic of Baotou Central Hospital from November 2017 to June 2018, and got a diagnosis in accordance with the 2014 diagnostic criteria for epilepsy published by International League Against Epilepsy and confirmed by video electroencephalogram and cranial MRI. DNA sequencing was used to analyze the distribution of MRP1 polymorphisms. Enzyme-linked immunosorbent assay was applied to measure serum MRP1 concentrations. Chemiluminescence was used to determine blood concentrations of carbamazepine and valproate in the epileptic patients.Results DNA sequencing showed that single nucleotide polymorphism was not found at 128 bp and 3173 bp of the MRP1 gene, but present at 218 bp and 2168 bp, in the AEDs-resistant patients and AEDs-sensitive patients. Five patients carried a C218T (rs41494447) mutation, with four in the AEDs-resistant group and one in the AEDs-sensitive group, and there was no significant difference in the distribution of C218T (rs41494447) polymorphism between the two groups (P>0.05). Nine cases harbored a G2168A (rs4148356) mutation, with six in the AEDs-resistant group and three in the AEDs-sensitive group, showing a significant difference in the distribution of G2168A (rs4148356) polymorphism between the two groups (P<0.05); the proportion of GA genotype was higher in the AEDs-resistant group (67%) than in the AEDs-sensitive group (33%). The concentration of MRP1 in the AEDs-resistant group was significantly higher than that in the AEDs-sensitive group (P<0.05). No significant difference was observed in MRP1 concentration between patients with different genotypes of C218T (rs41494447) or G2168A (rs4148356) (both P>0.05). The patients carrying GA genotype at 2168 bp of the MRP1 gene had significantly lower plasma concentrations of carbamazepine and valproate than those carrying GG genotype (P<0.05).Conclusions The polymorphism of G2168A (rs4148356) of the MRP1 gene may be responsible for AED resistance in epileptic patients, instead of G128C (rs41395947), C218T (rs41494447), and G3173A (rs41410450). The high expression of MRP1 may be one of the factors leading to drug resistance in epileptic patients, and is less likely to be the result of mutation at 218 bp or 2168 bp of the MRP1 gene. The patients with G2168A polymorphism tend to be resistant to carbamazepine and valproate.