OBJECTIVES: Epilepsy produces a significant burden on health care systems worldwide. Focal epilepsy represents approximately 70% of all types of epilepsy. The International League Against Epilepsy (ILAE) defined drug-resistant epilepsy in 2009 as a failure to achieve sustained seizure freedom, despite adequate trials of two tolerated and appropriately chosen and used antiepileptic drug (AED) schedules whether as monotherapies or in combination.The objective of this study was to estimate the economic impact of AED resistance in Spanish patients with focal epilepsy. METHODS: A multicentre, observational, cross-sectional, retrospective study was conducted in Spain among a representative sample of adults with focal epilepsy receiving at least two AEDs in combination, regardless of the seizure-free status. Investigators were hospital-based general neurologists and epileptologists; patients were consecutively included. Health resources utilisation data were collected over a retrospective 12-month period. Estimation of direct costs was calculated by multiplying unitary costs (at National Health System- NHS- values for the year 2010) by resource use from a NHS perspective. RESULTS: A total of 263 evaluable patients were analysed (out of 304 recruited patients, 86.5%). Responsiveness to AED treatment was assessed: 71% of the patients were AED resistant, 24% achieved seizure freedom and 5% were undefined. On average, resistant patients received more AEDs compared to seizure-free patients: 2.7 versus 2.4, respectively (p=0.0037). Annual costs for AED resistant and seizure-free patients were 4419€ and 3228€ respectively (37% increase per patient/year; p=0.0273). Drug costs (57%) and hospitalisation costs (33%) accounted for 90% of the incremental costs of AED resistant patients. CONCLUSIONS: Results suggest that drug resistant epilepsy is associated with higher health care use and consequently with higher costs, thus representing a considerable burden to the National Health System.