The current study sought to explore the association between primary caregiver depressive symptoms and the psychological functioning in children vertically infected with human immunodeficiency virus (HIV) living in Eastern Cape, South Africa. A cross-sectional data were collected using the Beck Depression Inventory and Strength and Difficulties Questionnaire in a sample of 152 caregiver/child dyads. The results revealed that poorer psychological functioning in children was significantly associated with depressive symptoms in caregivers. This relationship existed whether or not the child was raised by a biological or non-biological caregiver as well as for both genders. Younger children’s psychological functioning was more negatively influenced than that of older children raised by a caregiver with depressive symptoms. In the context of a large treatment gap for common mental disorders in South Africa, there is a need for interventions to address maternal mental health in families infected and affected by the HIV/AIDS pandemic as a mental health promotion strategy given that HIV-infected children are a particularly vulnerable population for poor mental and behavioural health outcomes.