OBJECTIVES: To explore possible explicative variables of health and non-health costs related with patient's life and treatment management in adult patients with refractory epilepsy in Spain. METHODS: A cross-sectional and retrospective study was designed. Male and female adult patients (above 18 years) with refractory epilepsy were enrolled in neurology medical settings between March and September 2005 in Spain. Health care and non-health care resources were collected and total costs calculated according with published prices for year 2005. Quality-of-life, level of anxiety and depression, health state, concomitant medications and comorbidity history and treatment of epilepsy were also recorded. A secondary analysis including a forward stepwise multivariate regression model exploring possible explicative variables was performed. RESULTS: Seven-hundred-sixty-two consecutive patients [728 evaluables (95.5%); 50.8% males, 40.5 (13.5) years, 24.3 (13.4) years of evolution] were included through the country at epilepsy units, neurology outpatient clinics and hospital outpatient clinics. A moderate explicative model was built; adjusted R-square=0.24 (F=26.6, p<0.0001). Presence of mental retardation and social function domain of the QOLIE-10 were the variables with most explicative weight of total cost in these patients; standardized estimates of 0.303 and 0.175, respectively [â coefficient (standard error) of 6675.0 (826.8) and 53.5 (12.7), p<0.001 in both cases respectively]. Health status on a 0-100 mm-VAS (standardized estimate; 0.142), need for additional non-neurological hospital assistance (0.118), previous episode of secondarily generalized seizures (0.102), health care at neurology outpatient clinics (0.083), and documented etiology of epilepsy (0.096) were all found to be significant explicative variable, all of them p<0.05. CONCLUSION: This secondary analysis found a broad sources of drivers of costs in patients with refractory epilepsy in Spain, with mental retardation and social function domain of QOLIE-10 (the higher the score the higher the cost) being responsible for a substantial part of total cost.