The objective of this study was to examine the relationship between adherence to treatment with sodium channel blockers (SCBs) and health-related quality of life (HRQoL), work productivity and activity impairment (WPAI), healthcare resource utilization (HRU), and associated costs among patients with epilepsy.This retrospective cross-sectional study used data from the 2017 US National Health and Wellness Survey (NHWS; N = 75,004). Health-related quality of life (Study Short-Form 36-Item Health Survey version 2 [SF-36v2]), WPAI (Work Productivity and Activity Impairment-General Health [WPAI-GH] questionnaire), HRU, and annual costs were compared among respondents with epilepsy using SCBs categorized as low/medium adherence (n = 120) and high adherence (n = 80) using generalized linear models, controlling for patient characteristics.Mental component score, Short-Form 6-Dimension (SF-6D) health utility index, bodily pain, mental health, physical functioning, role emotional, social functioning, and vitality scores were significantly lower in low/medium adherence respondents than in high adherence respondents (for all, p < 0.05). Only activity impairment was significantly higher in low/medium adherence respondents compared with the high adherence group (p < 0.001). Healthcare resource utilization did not differ significantly between the two groups; however, the number of emergency room (ER) visits and total costs were lower in the high adherence group (p = 0.038) compared with the low/medium adherence group (p = 0.040).High adherence to SCBs was associated with improved HRQoL, lower WPAI, and lower HRU and associated costs among patients with epilepsy. Therefore, adherence to SCBs may be an important factor in improving the abovementioned patient-reported outcomes. Findings from this study can help provide further impetus to healthcare policymakers and clinicians for addressing the low antiepileptic drug (AED) adherence levels in adult patients with epilepsy.