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Substantial resources are invested in psychological support for children orphaned or otherwise made vulnerable in the context of HIV/AIDS (OVC). However, there is still only limited scientific evidence for greater psychological distress amongst orphans and even less evidence for the effectiveness of current support strategies. Furthermore, programmes that address established mechanisms through which orphanhood can lead to greater psychological distress should be more effective. We use quantitative and qualitative data from Eastern Zimbabwe to measure the effects of orphanhood on psychological distress and to test mechanisms for greater distress amongst orphans suggested in a recently published theoretical framework. Orphans were found to suffer greater psychological distress than non-orphans (sex- and age-adjusted co-efficient: 0.15; 95% CI 0.03-0.26; P=0.013). Effects of orphanhood contributing to their increased levels of distress included trauma, being out-of-school, being cared for by a non-parent, inadequate care, child labour, physical abuse, and stigma and discrimination. Increased mobility and separation from siblings did not contribute to greater psychological distress in this study. Over 40% of orphaned children in the sample lived in households receiving external assistance. However, receipt of assistance was not associated with reduced psychological distress. These findings and the ideas put forward by children and caregivers in the focus group discussions suggest that community-based programmes that aim to improve caregiver selection, increase support for caregivers, and provide training in parenting responsibilities and skills might help to reduce psychological distress. These programmes should be under-pinned by further efforts to reduce poverty, increase school attendance and support out-of-school youth.