Caring for children can be a source of joy and fulfilment, but also a source of stress, especially for caregivers living with illness and/or coping with difficult socio-economic conditions. Risks for poor caregiver mental health are especially salient in many parts of southern Africa affected by a generalised HIV epidemic, high rates of physical illness, difficult livelihood conditions and an increasing number of orphaned and vulnerable children in need of care. Given limited availability and low uptake of formal mental health services in South Africa, the potential protective role of informal community or ‘social’ resources for caregiver populations requires greater attention. To our knowledge, this is the first study to quantitatively assess the relationship between social support and symptomatic anxiety among caregivers of children living in HIV-endemic southern African communities. The data are from household survey interviews with 2477 adult primary caregivers of children aged 10-17 years living in two (urban and rural) resource-deprived HIV-endemic South African communities. Hierarchical logistic regression analysis with interaction terms was conducted to assess whether HIV and other illness were significant stressors for caregiver anxiety, whether social support had main or stress-buffering protective effects on anxiety, and whether gender moderated the association between social support and anxiety. Our findings showed significant main effects of social support on caregiver anxiety, but no evidence of stress-buffering effects of support or of gender moderating the support-anxiety relationship. This suggests that social support is a general mental health resource for both male and female caregivers of children in these HIV-endemic communities, regardless of whether they are facing specific stressors related to HIV or other illness. Our results highlight the importance of paying greater attention to the social environment when designing and implementing caregiver health interventions, and indicate that social support could be a valuable component of such interventions.