Although epilepsy is associated with substantial role impairment, it is also highly comorbid with other physical and mental disorders, making unclear the extent to which impairments associated with epilepsy are actually due to comorbidities. This issue was explored in the National Comorbidity Survey Replication (NCS-R), a nationally representative household survey of 5692 US adults. Medically recognized epilepsy was ascertained with self-report, comorbid physical disorders with a chronic conditions checklist, and comorbid DSM-IV mental disorders with the Composite International Diagnostic Interview. Lifetime epilepsy prevalence was estimated at 1.8%. Epilepsy was comorbid with numerous neurological and general medical conditions and with a sporadic cluster of mental comorbidities (panic, PTSD, conduct disorder and substance use disorders). Although comorbid disorders explain part of the significant gross associations of epilepsy with impairment, epilepsy remains significantly associated with work disability, cognitive impairment and days of role impairment after controlling comorbidities. The net association of epilepsy with days of role impairment after controlling for comorbidities is equivalent to an annualized 89.4 million excess role impairment days among US adults with epilepsy, arguing that role impairment is a major component of the societal costs of epilepsy per se rather than merely due to disorders comorbid with epilepsy. This estimated burden is likely conservative as some parts of the effects of epilepsy are presumably mediated by secondary comorbid disorders.