Epilepsy in childhood extends far beyond seizures and affects child and parental well-being. The long-term impact of childhood-onset epilepsy on parental well-being is unknown. This study assessed health-related quality of life (HRQOL) in mothers 10 years after their child's diagnosis of epilepsy. Data come from the Health-Related Quality of Life in Children with Epilepsy Study, a multicenter prospective cohort study of children with newly diagnosed epilepsy. Mothers completed a mailed questionnaire at the 10-year follow-up, which included the Short-Form Health Survey (SF-12-v2) to evaluate the physical and mental health components of their HRQOL. Block-wise linear regressions identified child/epilepsy, maternal/family, and maternal psychosocial factors associated with mothers' HRQOL. A total of 159 mothers participated in this study (46% of the sample assessed at baseline). At follow-up, 69% of youth had been seizure free for the past 5 years. Mothers scored similarly to population norms (mean: 50, SD: 10) on the mental health subscale (mean: 49.5, SD: 9.3) and significantly better on the physical health subscale (mean: 53.0, SD: 7.6). Better family resources were associated with higher (better) scores on the physical health subscale (B = 0.20; 95% CI 0.03, 0.36). Better family functioning (B = 0.34; 95% CI 0.06, 0.62), fewer maternal depressive symptoms (B = 0.33; 95% CI 0.20, 0.47), and perception of less stress (B = 0.70; 95% CI 0.52, 0.88) were associated with higher (better) scores on the mental health subscale. Ten years after the diagnosis of epilepsy in children, the HRQOL of mothers was similar to reports from women in the general population. This study identified factors contributing to better maternal HRQOL and highlights the importance of family environment over epilepsy-related variables.