OBJECTIVES: Uncontrolled epilepsy is associated with devastating injuries, neuropsychiatric impairment, and increased mortality based on clinical observations. The purpose of this study is to evaluate the clinical and economic burden of uncontrolled epilepsy in a Medicaid population. METHODS: Medical and pharmacy claims from Florida (1997Q3-2008Q2), Iowa (1998Q1-2006Q2), Kansas (2001Q1-2009Q2), Missouri (1997Q1-2008Q2), and New Jersey (1997Q1-2008Q4) Medicaid databases were analyzed. Patients ≥18 years with epilepsy and receiving antiepileptic drugs (AEDs) were selected. A retrospective matched-cohort design was used to classify patients into mutually-exclusive cohorts of “uncontrolled” (≥2 consecutive AED changes followed by ≥1 epilepsy-related inpatient/ER visit), “well-controlled” (no AED change and no epilepsy-related inpatient/ER visit) and “intermediate” (neither “uncontrolled” nor “well-controlled”) epilepsy. Patients with uncontrolled epilepsy were matched 1:1 with those with well-controlled and intermediate epilepsy, respectively, using propensity score matching. Matched cohorts were compared for health care resource utilization, occurrence of negative clinical events, and direct health care costs. Statistical differences between cohorts were assessed using multivariate conditional regression models, adjusted for demographics, treatment characteristics, and comorbidities. RESULTS: Uncontrolled epilepsy was associated with significantly higher health care resource utilization (adjusted rate ratios [ARRs] [95% confidence intervals (95%CIs)]: hospitalizations=6.65 [6.41-6.90], length of hospital stays=7.72 [7.60-7.84], emergency-room visits=3.67 [3.61-3.74], outpatient visits=3.85 [3.77-3.93]) versus well-controlled epilepsy. Morbidity occurred more frequently in the uncontrolled group (ARRs: fractures: 2.16 [2.07-2.26], motor vehicle accident-related injuries: 2.45 [1.77-3.40], head injuries: 2.09 [2.04-2.14], status epilepticus events: 9.71 [8.20-11.50]) relative to well-controlled patients. Patients with uncontrolled epilepsy also incurred higher health care costs (adjusted cost difference [95%CI]=$12,258 [$10,482-$14,083] per patient per year), of which hospitalization costs represented 46.3%. Results were similar when compared to intermediate epilepsy. CONCLUSIONS: Uncontrolled epilepsy was associated with significantly greater health care resource utilization, higher rates of morbidity, and higher medical costs compared to well-controlled and intermediate epilepsy.