Objective To examine the level of depressive symptoms and their predictors in youth from one region of Rwanda who function as heads of household (ie, those responsible for caring for other children) and care for younger orphans. Design Cross-sectional survey Setting Four adjoining districts in Gigonkoro, an impoverished rural province in southwestern Rwanda. Participants Trained interviewers met with the eldest member of each household (n = 539) in which a youth 24 years old or younger was caring for 1 child or more. Main Exposure Serving as a youth head of household. Main Outcome Measures Rates and severity of depressive symptoms using the Center for Epidemiologic Studies Depression scale; measures of grief, adult support, social marginalization, and sociodemographic factors using scales developed for this study. Results Of the 539 youth heads of household, 77% were subsistence farmers and only 7% had attended school for 6 years or more. Almost half (44%) reported eating only 1 meal a day in the last week, and 80% rated their health as fair or poor. The mean score on the Center for Epidemiologic Studies Depression scale was 24.4, exceeding the most conservative published cutoff score for adolescents. Multivariate analysis revealed that reports of depressive symptoms that exceeded the clinical cutoff were associated with having 3 basic household assets or fewer, such as a mattress and a spare set of clothes (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.06-2.70), eating less than 1 meal per day (OR, 1.68; 95% CI, 1.09-2.60), reporting fair health (OR, 1.32; 95% CI, 0.76-2.29) or poor health (OR, 2.33; 95% CI, 1.17-4.64), endorsing high levels of grief (OR, 2.67; 95% CI, 1.73-4.13), having at least 1 parent die in the genocide as opposed to all other causes of parental death (OR, 1.83; 95% CI, 1.10-3.04), and not having a close friend (OR, 1.91; 95% CI, 1.17-3.12). There was an interaction between marginalization from the community and alcohol use; youth who were highly marginalized and did not drink alcohol were more than 3 times more likely to report symptoms of depression (OR, 3.07; 95% CI, 1.73-5.42). When models were constructed by grouping theoretically related variables into blocks and controlling for other blocks, the emotional status block of variables (grief and marginalization) accounted for the most variance in depressive symptoms. Conclusions Orphaned youth who head households in rural Rwanda face many challenges and report high rates of depressive symptoms. Interventions designed to go beyond improving food security and increasing household assets may be needed to reduce social isolation of youth heads of household. The effect of head-of-household depressive symptoms on other children living in youth-headed households is unknown.