To assess differences in psychosocial wellbeing between recent orphans and non-orphans, we followed a cohort of 157 school-going orphans and 480 non-orphans ages 9-15 in a context of high HIV/AIDS mortality in South Africa from 2004 to 2007. Several findings were contrary to published evidence to date, as we found no difference between orphans and non-orphans in anxiety/depression symptoms, oppositional behavior, self-esteem, or resilience. Female gender, self-reported poor health, and food insecurity were the most important predictors of children’s psychosocial wellbeing. Notably, girls had greater odds of reporting anxiety/depression symptoms than boys, and scored lower on self-esteem and resilience scales. Food insecurity predicted greater anxiety/depression symptoms and lower resilience. Perceived social support was a protective factor, as it was associated with lower odds of anxiety/depression symptoms, lower oppositional scores, and greater self-esteem and resilience. Our findings suggest a need to identify and strengthen psychosocial supports for girls, and for all children in contexts of AIDS-affected and economic adversity.