OBJECTIVES:  This retrospective analysis of healthcare claims data was conducted to examine healthcare costs in patients with probable Lennox-Gastaut syndrome (LGS) treated with clobazam (CLB). METHODS:  Patients with likely LGS were identified from epilepsy patients (≥2 claims for epilepsy [ICD-9-CM 345.xx] or unspecified epilepsy [ICD-9-CM 780.39]) in 6 state Medicaid databases using a random forest machine-learning algorithm. CLB users were defined as having ≥2 prescription claims for CLB and ≥1 year of continuous enrollment before CLB initiation (index date). Monthly healthcare costs were estimated for pre-CLB (1 year before index date) and post-CLB (to end of data availability) periods. Generalized estimating equations were used to characterize and predict time trends before and after CLB initiation. To estimate the impact of CLB use on healthcare costs, the slope of monthly costs before CLB initiation was extrapolated beyond the index date and compared to post-CLB costs. The difference was quantified by calculating areas under the curve (AUCs). RESULTS:  A total of 1,301 likely LGS patients were identified. Mean (SD) duration of observation post-CLB initiation was 1.60 (0.86) years. When compared to extrapolated costs without CLB during the post-CLB period, CLB treatment was associated with significant reductions in total all-cause, total epilepsy-related, and inpatient medical costs (P<0.05), and a nonsignificant increase in home care costs (P=0.45). The difference in AUCs was equivalent to a reduction of $1,538.89 (3.80%) in all-cause healthcare costs in the year after CLB initiation, and reductions of $2,236.34 (11.99%) and $3,112.29 (26.66%) for total epilepsy-related and inpatient costs, respectively. The cost increase for home care was $1,839.74 (11.62%). CONCLUSIONS:  Results from this study indicate that CLB initiation in LGS patients is associated with reduced healthcare costs, mainly driven by lower inpatient costs. Funded by Lundbeck