Background/Purpose Among adolescents, mental health is significantly associated with quality of interpersonal relationships. The relationship can be mediated by factors such as socio-economic status, family processes and social stressors. The purpose of this study was to examine the relationship between family structure and mental health status among Ghanaian youth. Method Data from the 2008 Ghana Global School-based Student Health Survey was utilized. Complex sample logistic regression analysis was used to examine the relationship between family structure (guardian[s]) and the following; loneliness, anxiety, signs and symptoms of depression, suicide ideation, and suicide planning. Control variables were gender, number of close friend(s), and parental understanding of problems. Analysis/Results Overall, students being raised by both parents are significantly less likely to report being lonely, anxious, signs and symptoms of depression, suicide ideation and suicide plan compared to students in other types of family structures. Students being raised primarily by a father were 1.4 (95% CI: 1.1-1.7) times more likely to report being lonely, 1.8 (95% CI: 1.3-2.4) times more likely to report being anxious, and 1.3 (98% CI: 1.1-1.5) times more likely to signs and symptoms of depression. Overall, odds of reporting mental health problems were much higher for students being raised by a person who is not an immediate family member. Conclusions The association between family structure and mental health indicates a need to concurrently examine family dynamics as part of any psychosocial health intervention among Ghanaian high school students.