Background: Supportive relationships provide positive affect and a sense of belonging, which enable positive mental health outcomes. Objective: This study examines the association between the quality of the relationship of youth in Residential Care (RC) with their best friend and their mental health, considering the moderator role of gender and age and the context of friendship (in/outside RC) in these associations. Method: Participants were 752 youth (46.4% girls), aged 11-25 years (M = 16.19, SD = 2.25), and their main caregiver. Youth filled out the Network of Relationships Inventory to evaluate their relationship quality with their best friend through six conceptually distinct, though interrelated, dimensions (companionship, intimate self-disclosure, emotional support, satisfaction, conflict and criticism), while their main residential caregiver completed the Child Behaviour Checklist (internalizing and externalizing problems). Results: Younger youth with higher levels of perceived emotional support have fewer internalizing problems, compared to older youth. Boys with higher perceived companionship are described as having lower levels of internalizing problems compared to girls. Girls with higher perceived intimate disclosure are described as having lower levels of internalizing problems, compared to boys. And girls with higher perceived conflict are described as having higher levels of externalizing problems, compared to boys. Conclusions: The findings add to existing evidence on the association between quality friendship relationships and youth's mental health, by highlighting the moderating role of youth's age and gender in that associations.