Ehlers-Danlos Syndrome (EDS) is a group of related genetic disorders of connective tissue presenting with joint hypermobility, skin extensibility, and tissue fragility. Although the pathophysiology of EDS is increasingly understood, the psychosocial effects of having EDS have not been examined. We psychologically tested and interviewed 41 adults and 7 children with EDS. Anxiety, depression, anger, and interpersonal concerns were significantly elevated, varying from one-quarter to one-third of patients; over 70% had a history of some mental health care use. Psychological difficulties appear to result from chronic pain and disability, ostracism or avoidance of relationships and social activities, sexual difficulties and reproductive concerns, and frustration with the medical system. Specific types of EDS (e.g., EDS Type I) are associated with greater pain and psychological distress. Psychological intervention, prescribed with the recognition that psychiatric features are secondary to EDS, is recommended for some patients.