Previous population surveys outside the United States have found an increased prevalence of comorbid conditions in persons with epilepsy. However, the effect of comorbid conditions on health-related quality of life (HRQOL) has not been previously examined in the epilepsy literature from the United States. Results from the California Health Interview Survey (CHIS) indicate an increased prevalence of comorbid conditions in persons with a history of epilepsy compared to those without epilepsy. After controlling for demographics and comorbid conditions, persons with a history of epilepsy were significantly more likely to report poor HRQOL. Although seizure freedom should continue to be a primary clinical goal, optimal care should also include primary and secondary prevention of comorbid conditions, especially cardiovascular and pulmonary diseases. Prevention, early identification, and treatment of comorbid conditions may reduce mortality risk and improve health outcomes in persons with epilepsy.