According to research children living with HIV experience elevated levels of depression, anxiety, ADHD and disruptive behavioural disorders. Although South Africa’s paediatric population that is infected with the human immunodeficiency virus (HIV) is the largest worldwide, little research has been conducted on their mental health challenges. However, attributing high levels of mental health problems solely to their HIV status can be problematic as there may be other contributory factors. This research explored the mental health problems of HIV-infected children and compared these to the mental health problems of their HIV-unaffected peers from similar backgrounds. Data was gathered from two samples of child and caregiver pairs. HIV-infected children (aged 6–12 years) and their caregivers/mothers (n = 54) were recruited from the Kalafong paediatric clinic where they received medical treatment and routine ART. A comparison group of 113 HIV-uninfected children and their uninfected mothers were recruited from primary care clinics in the same community. Caregivers completed the Child Behaviour Checklist (CBCL) to assess children’s mental health. Children completed the Self-Description Questionnaire (SDQ-I) and the Revised Children’s Manifest Anxiety Scale (RCMAS). The scores of the psychometric sub-scales of the two groups were compared using parametric and non-parametric statistics. HIV-infected children experienced more somatic and affective problems, physiological anxiety, less ADHD and lower self-esteem than HIV-uninfected children in the comparison group, while controlling for age differences. The high levels of mental health problems of both groups of children may be attributed to similar difficult socio-economic circumstances. The fact that most infected children were not aware of their HIV-status could have influenced the results. Mental health services should not be limited to HIV-infected children but should form part of all health care services.