This pilot study assessed the quality of life and psychosocial functioning of pediatric patients with Barth Syndrome. Thirty-four boys with Barth Syndrome and 22 healthy male controls were administered a measure of verbal ability and completed measures of quality of life, loneliness, perceived peer support, and sibling relationship quality. Parents completed measures of parental distress, parenting stress, child academic functioning, child adaptive behavior, and child emotional and behavioral functioning. Quality of life ratings were consistently lower in youth with Barth Syndrome relative to both healthy controls and a previously reported sample of youth with cardiac disease. Compared to healthy controls, children with Barth Syndrome were rated as having more internalizing and externalizing symptoms, social problems, loneliness, and lower independent functioning. Parents of boys with Barth Syndrome reported greater distress and parenting stress relative to healthy controls. In addition, parents reported a significant need for academic accommodations, given their son's illness and associated impairments. Boys with Barth Syndrome and their parents appear to be affected by the presence of the illness in numerous ways. Results suggest the need for interventions aimed at helping children and families cope with illness-related stressors to enhance quality of life and overall functioning.