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Youth experiencing mental health symptoms have been found to be more susceptible to e-cigarette initiation. Limited research has examined predictors of e-cigarette use through longitudinal analysis. Understanding how mental health symptoms influence later use is essential for developing effective prevention strategies targeting youth and young adults. This study contributes to the literature by investigating the association between mental health symptoms and e-cigarette initiation using a longitudinal design. Data were drawn from the Truth Longitudinal Cohort, a nationally representative, probability-based U.S. cohort (<i>N</i> = 4,058; 15-24 years). Respondents were nicotine naïve at baseline (Spring 2018) and had data at follow-up (Fall 2019) for variables of interest. Mental health status was collected at baseline with one item per symptom (i.e., sadness/depression, attention issues, sleep issues). E-cigarette use was measured between baseline and follow-up: "Have you ever used or tried any e-cigarettes or e-hookah?" Results revealed a significant positive relationship between mental health symptoms at baseline and future e-cigarette initiation. For each unit increase in participants' mental health symptoms' scale score, the odds of initiating electronic nicotine delivery systems (ENDS) by follow-up increased by .07, on average (odds ratio [<i>OR</i>] = 1.07, 95% confidence interval [CI] = [1.02, 1.11]). In addition, post hoc sensitivity analyses were run testing mental health score thresholds to evaluate the robustness of the relationship with ENDS initiation. Results revealed a significant relationship between those reporting "high" versus "low" mental health symptoms (<i>OR</i> = 1.54, 95% CI = [1.10, 2.14]). This study revealed the predictive relationship between mental health symptoms and future e-cigarette initiation.