OBJECTIVES: Adherence to antiepileptic drugs (AEDs) is imperfect and AEDs of long half-life or duration of action (e.g., extended release) might mitigate the impact of missed doses. We compared costs and utilization between patients treated with long-acting (LA) and short-acting (SA) AED monotherapy. METHODS: A retrospective cohort analysis was conducted using claims data (OptumInsight).  We included adult epilepsy patients (≥1 epilepsy diagnosis in 2010 and 2011) who used AED monotherapy and were continuously enrolled in 2011.  Patients were excluded if they had <2 AED fills, <9 months of treatment, or a treatment gap >60 days. Based on published data and expert opinion, AEDs were classified as LA or SA.  Pharmacy and medical claims in 2011 were used to determine costs and utilization.  Claims associated with an epilepsy diagnosis, test, or AEDs were considered epilepsy-related.  Baseline group differences were adjusted using multivariate analyses. RESULTS: The 4058 (49.6%) LA users and 4122 (50.4%) SA users were mean age: 47.7 vs. 45.1 years, female: 47.6% vs. 57.0%; and had epilepsy-specific comorbidities: 19% vs. 25%, respectively; all P<0.001. Compared with SA users, LA users had lower mean overall costs ($9,757 vs. $12,689) and epilepsy-related costs ($3,539 vs. 5,279) and lower rate of overall (8.7% vs. 10.8%) and epilepsy-related hospitalization (5.7% vs. 7.5%) (all P <0.01).  After adjusting for demographics, usual care physician, and comorbidities, mean overall costs were lower by $686 (P=0.137) and mean epilepsy-related costs by $894 (P=0.005) in LA users than in SA users. CONCLUSIONS: Patients with epilepsy treated with LA AED monotherapy incur a lower economic burden than those treated with SA AED monotherapy. This study indicates that using AEDs with more extended coverage between doses may decrease health care use and lower costs. Future studies should examine the impact of duration of action on outcomes in combination therapy and in adolescents.