Objective: The results from studies investigating a possible association between ABCB1 polymorphism and drug-resistant epilepsy are so far inconsistent. Moreover, recent meta-analyses studies do not confirm any link between ABCB1 C3435T polymorphism and drug resistance. Yet, if patients with comparable clinical status (same type of epilepsy, antiepileptic drugs, epilepsy onset and gender) are evaluated, the link between ABCB1 polymorphisms and drug resistance may be unmasked. We studied the association between C3435T and G2677T/A ABCB1 gene polymorphisms and drug resistance in Iranian epilepsy patients.Methods: Two hundred healthy subjects and 332 epilepsy patients (200 drug-responsive and 132 drug-resistant) were selected. Genotypes were determined by polymerase chain reaction followed by restriction fragment length polymorphism or the amplification refractory mutation system.Results: The risk of drug resistance was higher in patients with a C/T genotype than in those with C/C or T/T genotypes at position 3435 in patients with cryptogenic epilepsy (p=0.01). A higher risk of drug resistance was observed in adult patients with a C/C genotype than in those with a T/T genotype at position 3435 (25.8% vs 15.8%, p=0.01). The risk of drug resistance was also higher in female patients with a C/C genotype than in those with a T/T genotype at position 3435 (26.8% vs 16.3%, p=0.04). No significant association was found between G2677T/A polymorphism and epilepsy drug resistance in the different subgroups of patients.Conclusion: Iranian adult female patients with a C/C genotype at position 3435 of the ABCB1 gene have a higher risk of resistance to antiepileptic drugs. Replication studies with large sample sizes are needed to confirm the results.