Background: Depressed mood has been associated with decreased white matter and reduced hippocampal volumes. However, the relationship between brain structure and mood may be unique among adolescents who use marijuana heavily. The goal of this study was to examine the relationship between white matter and hippocampal volumes and depressive symptoms among adolescent marijuana users and controls. Methods: Data were collected from marijuana users (n = 16) and demographically similar controls (n = 16) aged 16-18. Extensive exclusionary criteria included psychiatric and neurologic disorders, including major depression. Substance use, mood, and anatomical measures were collected after 28 days of monitored abstinence. Results: Marijuana (MJ) users demonstrated more depressive symptoms than controls (p less than 0.05). MJ use (beta = 0.42, p less than 0.005) and smaller white matter volume (beta = 0.34, p less than 0.03) each predicted higher levels of depressive symptoms on the "Hamilton Depression Rating Scale." MJ use interacted with white matter volume (beta = 0.55, p less than 0.03) in predicting depression scores on the "Beck Depression Inventory": among MJ users, but not controls, white matter volume was negatively associated with depressive symptoms. Conclusions: Marijuana use and white matter volume were additive and interactive in predicting depressive symptoms among adolescents. Subtle neurodevelopmental white matter abnormalities may disrupt the connections between areas involved in mood regulation.