Over the past decade, the effects of AIDS-related parental death on children's socio-economic, educational and psychological well-being have become apparent. Most studies, however, have compared the plight of so-called AIDS orphans with non-orphaned children only. Consequently, such study designs are unable to establish if the AIDS-related cause of death of the parents confers effects additional to those of parent-bereavement. We therefore conducted a cross-sectional survey to assess the psychological well-being and socio-economic hardship among 140 non-orphaned children, 133 children orphaned by causes other than AIDS (O) and 124 children orphaned by AIDS (O-A) in Conakry, N'Zerekore and the villages around N'Zerekore, Guinea. Multi-way analysis of variance and multiple (ordinal) logistic regression models were applied to measure the association between the orphan status and psychological well-being, school attendance, economic activities, frequency of going to bed hungry and sleeping commodity. After adjustment for confounding factors, the psychological well-being score (PWS) was significantly lower among AIDS-orphaned children than among O (P<0.001). Additionally, AIDS-orphaned children were more likely to be engaged in economic activities (adjusted odds ratio (AOR) = 3.04; 95% CI: 1.45-6.36) and to go to bed hungry on a daily basis (AOR = 2.73; 95% CI: 1.24-6.02) than other orphans. The differences in school attendance and the proportion of children with a bed or couch to sleep between AIDS-orphaned children and O were not statistically significant. This situation calls for sustainable and holistic approaches to ensure the psychological and socio-economic stability of AIDS orphans and other vulnerable children.