Runaway youth report a broader range and higher severity of substance-related, mental health and family problems relative to non-runaway youth. Most studies to date have collected self-report data on the family and social history; virtually no research has examined treatment effectiveness with this population. This study is a treatment development project in which 124 runaway youth were randomly assigned to (1) ecologically based family therapy (EBFT) or (2) service as usual (SAU) through a shelter. Youth completed an intake, posttreatment, 6 and 12 months follow-up assessment. Youth assigned to EBFT reported greater reductions in overall substance abuse compared to youth assigned to SAU while other problem areas improved in both conditions. Findings suggest that EBFT is an efficacious intervention for this relatively severe population of youth.