The purpose of this study was to test a diathesis-stress model of well-being for siblings who have a brother or sister with an autism spectrum disorder (ASD). Data were collected from 57 adolescents and their mothers. Sisters reported higher levels of depressive and anxiety symptoms than brothers. Having a family history of ASDs was associated with depressive, but not anxiety, symptoms. A high level of maternal depression was also associated with more depressive and anxiety symptoms. A diathesis-stress model was partially supported, primarily through the findings that sibling sub-threshold autism characteristics were associated with depressive and anxiety symptoms in siblings, but only in the presence of a high number of stressful life events.