Objective: Neuroimaging findings have been reported in regions of the brain associated with emotion in both adults and adolescents with depression, but few studies have investigated whether such brain alterations can be detected in adolescents with subthreshold depression, a condition at risk for major depressive disorder. In this study, we searched for differences in brain structure at age 14 years in adolescents with subthreshold depression and their relation to depression at age 16 years. Method: High-resolution structural magnetic resonance imaging was used to assess adolescents with self-reported subthreshold depression (n = 119) and healthy control adolescents (n = 461), all recruited from a community-based sample. Regional gray and white matter volumes were compared across groups using whole-brain voxel-based morphometry. The relationship between subthreshold depression at baseline and depression outcome was explored using causal mediation analyses to search for mediating effects of regional brain volumes. Results: Adolescents with subthreshold depression had smaller gray matter volume in the ventromedial prefrontal and rostral anterior cingulate cortices and caudates, and smaller white matter volumes in the anterior limb of internal capsules, left forceps minor, and right cingulum. In girls, but not in boys, the relation between subthreshold depression at baseline and high depression score at follow-up was mediated by medial-prefrontal gray matter volume. Conclusion: Subthreshold depression in early adolescence might be associated with smaller gray and white matter volumes in regions of the frontal-striatal-limbic affective circuit, and the occurrence of depression in girls with subthreshold depression might be influenced by medial-prefrontal gray matter volume. However, these findings should be interpreted with caution because of the limitations of the clinical assessment methods.