OBJECTIVES: This study evaluated the impact of average antiepileptic drug (AED) pill burden during the year following initiation of monotherapy on epilepsy-related health care costs among patients with epilepsy in a large real-world setting in the United States. METHODS: A retrospective analysis of a large commercial claims database (January 1, 2006, to December 31, 2011) was conducted to assess average AED pill burden and its impact on epilepsy-related health care costs in adults with epilepsy. Patients aged 18-65 years with ≥2 epilepsy diagnoses and ≥2 AED prescription claims were selected for study inclusion. The first AED claim defined the index date, on which patients were required to have AED monotherapy. Patients had at least 6 and 12 months of continuous health plan enrollment before and after their index date, respectively. Generalized linear models were used to assess the relationship between average pill burden and epilepsy-related health care costs during the year following monotherapy initiation, adjusting for confounders. RESULTS: Of the 53,338 study patients, 6.4%, 14.7%, 31.4%, and 47.6% had an average of 0 - 1, >1 - 2, >2 - 3, and > 3 AED pills per day during the year following AED monotherapy initiation, respectively. Compared to those on 0-1 pills/day, adjusted annual epilepsy-related health care costs were incrementally higher among those on >2-3, or >3 pills/day (7.9% and 34.6%, respectively), and 15% lower among patients on >1-2 pills. The adjusted epilepsy-related mean per-person annual health care costs were estimated at $4,885 for all patients and $3,821, $3,270, $4,792, and $5,587 for patients prescribed an average of 0 - 1, >1 - 2, >2 - 3, and > 3 pills per day, respectively. CONCLUSIONS: Patients prescribed an average of fewer than 2 AED pills per day incurred lower epilepsy-related health care costs during the year following monotherapy.