Associations between multiple risks, emotion regulation skill, and basal cortisol levels were examined in a community sample of 69 African American youth (mean age = 11.30 years; 49% male) living in an urban setting. Multiple risks were assessed at Time 1 and consisted of 10 demographic and psychosocial risk factors including parent, child, and observer reports. Parents rated the child's emotion regulation skill at Time 2, 6 months later. Three saliva samples were collected one morning in the week following the Time 2 interview and assayed for cortisol, a stress hormone. Regression results indicated that multiple risks at Time 1 were associated with depressed cortisol levels at Time 2, but that patterns of association differed across levels of emotion regulation skill and sex. Youth with good emotion regulation skills showed no differences in cortisol across low and high levels of risk. In contrast, females with poor emotion regulation skill showed strong negative associations between multiple risks and basal cortisol levels. Hypocortisolism is a response of some youth to multiple risks, but protective factors can attenuate this association. (Contains 2 tables and 1 figure.)