Dysregulated hypothalamic-pituitary-adrenocortical (HPA) axis stress response has been reported among individuals with prenatal substance exposure and those with early adversity exposure. However, few researchers have examined the combined effects of these risk factors. Patterns of HPA reactivity among maltreated foster children with and without prenatal substance exposure (N = 53; ages 9-12 years) were examined using the Trier Social Stress Test for Children. Area under the curve with respect to increase (AUCI) analyses revealed that prenatal substance exposure or physical abuse significantly increased the likelihood of a negative AUCI (i.e., little or no HPA reactivity). Among children with prenatal substance exposure and physical abuse, 85% exhibited a negative AUCI. The results underscore the importance of addressing this combined risk. (Contains 2 tables and 2 figures.)