The high-risk children (n=76) were free of any lifetime affective disorder and had at least one first-degree and one second-degree relative with a lifetime history of childhood-onset, recurrent, bipolar, or psychotic depression. The low-risk children (n=63) were free of any lifetime psychiatric disorder and had no first-degree relatives and fewer than 20 percent of their second-degree relatives with a lifetime affective disorder. Children and their parents were assessed in a prospective design by using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic version. The average interval between follow-up interviews was 18 months, and the average follow-up period was 6 years. There were no significant differences in the retention rates between high-risk and low-risk children (93 percent compared with 95 percent). The demographic and follow-up characteristics of the two groups were compared by using t test and X-squared statistics as appropriate. The study found that high-risk children had approximately a threefold increased risk of developing first-onset MDD compared with the low-risk children (odds ratio=3.21). The average age of new-onset MDD was about 14 years. The mother's lifetime anxiety disorder and lifetime behavioral disorder in the child added significantly to the risk of developing a first-onset MDD. These findings suggest that clinicians who are treating adult patients should assess the mental health of their children. Future research will examine the contribution of various psychobiological and psychosocial predictors of first-onset MDD in this sample of children. Findings from this research should identify the mechanisms involved in converting a child's high-risk status into a clinical course of depression, which will be important knowledge for guiding effective interventions. 1 table, 1 figure, and 54 references