To date, universal, school-based interventions have produced limited success in the long-term prevention of depression in young people. This paper examines whether family relationship support moderates the outcomes of a universal, school-based preventive intervention for depression in adolescents. It reports a secondary analysis of data from the beyondblue schools research initiative. Twenty-five matched pairs of secondary schools were randomly assigned to an intervention or control condition (N = 5633 Grade 8 students). The multi-component, school-based intervention was implemented over a 3-year period, with 2 years of follow-up in Grades 11 and 12. For those available at follow-up, small but significantly greater reductions in depressive and anxiety symptoms and improvements in emotional wellbeing were found over time for the intervention group compared to the control among those who experienced low family relationship support in Grade 8. For those who did not experience low family relationship support in Grade 8, no significant effects of the invention were found over the control condition. This pattern of results was also found for the intent-to-treat sample for measures of depression and anxiety. Previous research may have overlooked important moderating variables that influence the outcome of universal approaches to the prevention of depression. The findings raise issues of the relative costs and benefits of universal versus targeted approaches to the prevention of depression.