IMPORTANCE The trajectory of cortical gray matter development in childhood has been characterized by early neurogenesis and volume increase, peaking at puberty followed by selective elimination andmyelination, resulting in volume loss and thinning. This inverted U-shaped trajectory, as well as cortical thickness, has been associated with cognitive and emotional function. Synaptic pruning-based volume decline has been related to experience-dependent plasticity in animals. To date, there have been no data to inform whether and how childhood depression might be associated with this trajectory. OBJECTIVE To examine the effects of early childhood depression, from the preschool age to the school age period, on cortical gray matter development measured across 3 waves of neuroimaging from late school age to early adolescence. DESIGN, SETTING, AND PARTICIPANTS Datawere collected in an academic research setting from September 22, 2003, to December 13, 2014, on 193 children aged 3 to 6 years from the St Louis, Missouri, metropolitan area who were observed for up to 11 years in a longitudinal behavioral and neuroimaging study of childhood depression. Multilevel modeling was applied to explore the association between the number of childhood depression symptoms and prior diagnosis of major depressive disorder and the trajectory of gray matter change across 3 scan waves. Data analysis was conducted from October 29, 2014, to September 28, 2015. MAIN OUTCOMES AND MEASURES Volume, thickness, and surface area of cortical gray matter measured using structural magnetic resonance imaging at 3 scan waves. RESULTS Of the 193 children, 90 had a diagnosis of major depressive disorder; 116 children had 3 full waves of neuroimaging scans. Findings demonstrated marked alterations in cortical gray matter volume loss (slope estimate, -0.93 cm3; 95%CI, -1.75 to -0.10 cm3 per scan wave) and thinning (slope estimate, -0.0044 mm; 95%CI, -0.0077 to -0.0012mmper scan wave) associated with experiencing an episode of major depressive disorder before the first magnetic resonance imaging scan. In contrast, no significant associations were found between development of gray matter and family history of depression or experiences of traumatic or stressful life events during this period. CONCLUSIONS AND RELEVANCE This study demonstrates an association between early childhood depression and the trajectory of cortical gray matter development in late school age and early adolescence. These findings underscore the significance of early childhood depression on alterations in neural development.