The aim of this study was to analyse the frequency of genotypes and alleles of single-nucleotide polymorphism (SNP)-G2677T/A (rs2032582) of MDR1 gene and to investigate the significance this genetic variation exerts on drug-resistant epilepsy (DRE) in the Polish adult population. The study comprised 340 patients treated for DRE and 240 patients treated for drug-responsive epilepsy. Three hundred and sixty disease-free individuals were used as controls. Genomic DNA was isolated, and the SNP G2677T/A of MDR1 was determined by High-Resolution Melter technique. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele. In this paper, we have demonstrated that A allele of SNP G2677T/A of MDR1 may reduce the risk of DRE (OR 0.44; 95% CI 0.33–0.58, p < 0.0001), whereas allele G itself may be a risk factor for this disease. No differences were found in the distribution of the genotypes and alleles in the studied groups, depending on sex as well as on concomitant diseases (p > 0.05). G2677T/A polymorphism of MDR1 may play a significant role in the development of DRE in the Polish patients.