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Purpose: To examine the prevalence, trajectories, and predictors of depressive symptoms (DS) in mothers of children with new-onset epilepsy. Methods: A sample of 339 mothers was analyzed from the health-related quality of life in children with epilepsy study assessed four times during the first 24 months after diagnosis. Mothers' DS were measured using the Center for Epidemiological Studies Depression Scale. Trajectories of DS were investigated using group-based trajectory modeling, and maternal, child, and family factors were compared across groups using analysis of variance (ANOVA) and chi square tests. Multinomial logistic regression identified predictors of DS trajectories. Key Findings: A total of 258 mothers completed the study. Prevalence of depression ranged from 30-38% across four times within the first 24 months after their child's diagnosis. Four trajectories of DS were observed: low stable (59%), borderline (25%), moderate increasing (9%), and high decreasing (7%). Using the low stable group as the reference group, the borderline group was younger, had worse family functioning, and fewer family resources; the moderate increasing group was younger, had children with cognitive problems, worse family functioning, and more family demands; and the high decreasing group had less education and children with lower quality of life. Significance: Risk for clinical depression is common among mothers of children with new-onset epilepsy. These mothers are not homogenous, but consist of groups with different trajectories and predictors of DS. Child's cognitive problems was the strongest predictor identified; epilepsy severity did not predict DS trajectory. Health care professionals should consider routinely assessing maternal depression during clinic visits for pediatric epilepsy. © 2010 International League Against Epilepsy.