The authors tested neighborhood context, negative life events, and negative affectivity as predictors of the onset of major depression among 720 African American women. Neighborhood-level economic disadvantage (e.g., percentage of residents below the poverty line) and social disorder (e.g., delinquency, drug use) predicted the onset of major depression when controlling for individual-level demographic characteristics. Neighborhood-level disadvantage/disorder interacted with negative life events, such that women who experienced recent negative life events and lived in high disadvantage/disorder neighborhoods were more likely to become depressed than were those who lived in more benign settings, both concurrently and over a 2-year period. Neighborhood disadvantage/disorder can be viewed as a vulnerability factor that increases susceptibility to depression following the experience of negative life events.