OBJECTIVES: The U.S. Food and Drug Administration’s decision to mandate a black-box warning on antidepressants indicating that they are associated with an increased risk of suicidal behavior in children and young adults remains controversial. We aimed to quantify the tradeoffs of alternative strategies in treating pediatric major depressive disorder (MDD) with respect to clinical benefit and risk of fatal and non-fatal suicidal behavior over a five-year time horizon. METHODS: We developed a disease simulation model integrating epidemiological and clinical data from the published literature in order to simulate the effect of three treatment strategies (i.e., Selective serotonin reuptake inhibitors (SSRIs), cognitive behavioral therapy (CBT), and a combination of SSRIs and CBT) on a U.S. population of children and young adults with MDD. We explored the implications of different scenarios of data extrapolation beyond the time horizon of existing data and of uncertain assumptions about suicide attempt risks and patients’ response to treatment. Main outcome measures were symptom-free weeks, suicide attempts, and suicide deaths. RESULTS: In a cohort of 1,000,000 simulated children and young adults, there were more than twice as many suicide deaths among those started on SSRIs (1291), compared to those started on CBT (506) or combination treatment (621) over the first 36 weeks of treatment. Over a five-year time horizon, this hierarchy of suicide risk persisted, even under assumptions most favorable to SSRIs. With respect to symptom-free weeks, combination treatment was superior to both SSRIs and CBT alone, but this difference was marginal over a five-year time horizon. CONCLUSIONS: Considering the risk-benefit profile over a five-year period, CBT appears to offer a safer profile with respect to suicide deaths and attempts than combination treatment or SSRIs alone. While combination treatment maximizes symptom-free weeks, the additional benefit over the five-year time horizon is modest and must be weighed against the clinically meaningful increase in fatal suicides.