Epilepsy is a common disorder affecting up to 1% of the population. Complex partial seizures (CPS) occur in about 35% of patients with epilepsy. Twenty percent of patients with CPS have uncontrolled seizures, refractory to anticonvulsant therapy. The etiology of epilepsy is often multifactorial, with 60-70% of all cases without clear cause, although much is known about the physiological bases of abnormal discharges accompanying seizure phenomena. It seems likely that there is a primary defect in the neuronal membrane that results in the instability of the resting membrane potential [1]. There is no clear biological Abstract Apolipoprotein E (ApoE) is a constituent of many types of lipoproteins that play a role in metabolism of cholesterol and lipids in the body as well as in the brain. ApoE is synthesised in astrocytes and microglia and enter to neurons through LDL, LRP and VLDL receptors. Recently it was shown that ApoE is also produced in neurons. ApoE has a role in modulating learning and memory, structural plasticity, mobilization of cholesterol in repair, growth and maintenance of myelin and neuronal membranes during development and aging, and cell death after ischemic, convulsive, or other type of brain injury. The aim of this research was to investigate the possible association of ApoE gene polymorphism with the development of resistance to pharmacological therapy in patients with partial complex seizures with or without secondary generalization. In this prospective matched-pair controlled study, 60 patients with cryptogenic epilepsy with complex partial seizures, with or without secondary generalization, who have been suffering for five or more years, were studied. The first group comprised 30 patients refractory to the current therapy, while the second group consisted of patients with well-controlled seizures. The refractory and non-refractory groups of patients differed significantly in their phenotypes. Phenotype E3/4 was six times more frequent in refractory group than among non-refractory group. The lack of response was shown to be significantly associated with the presence of ε4 allele. This study provided evidence that the presence of ε4 allele is more often associated with a lack of response to current antiepileptic drugs as compared to ε2 and ε3 alleles.