BACKGROUND: There is little knowledge about the psychosocial distress of children affected by human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) in Ghana, to aid the planning of services. This study investigated mental health problems among children affected by HIV/AIDS, compared with control groups of children orphaned by other causes, and non-orphans. METHOD: The study employed a cross-sectional survey that interviewed 291 children and their caregivers. Both children and caregivers completed the Strengths and Difficulties Questionnaire that measured children’s psychosocial wellbeing. Verbal autopsy was used to identify whether children lost one or both parents from AIDS. RESULTS: The results indicated that controlling for relevant sociodemographic factors, both children’s self-reports and caregivers’ reports indicate that both children living with HIV/AIDS-infected caregivers and children orphaned by AIDS were at heightened risk for mental health problems than both children orphaned by other causes and non-orphans. The findings further indicated that a significant proportion of orphaned and vulnerable children exhibited symptoms for depression and other psychiatric disorders (approximately 63%) compared with 7% among the non-orphaned group. Caregivers gave higher ratings for children on externalizing problems and lower on internalizing problems, and vice versa when the children’s self-reports were analysed. CONCLUSIONS: The findings suggest that both children and their informants have diverse yet complementary perspectives on psychological outcomes. The study discusses the theoretical and practical implications of these findings and urgently calls for necessary intervention programmes that target all children affected by HIV/AIDS to effectively alleviate psychological distress and enhance the mental health of these children.