Patients with Ehlers-Danlos Syndrome, hypermobile type (hEDS) often report a decrease of health-related quality of life (HRQoL), symptoms of anxiety and depression, and show a prevalent incidence of psychiatric disorders. Still, there seems to be a lack of a more thorough analysis addressing the relations between these entities. We studied the HRQoL and its relations with depressive symptoms and subgroups of anxiety in a group of patients with hEDS (<i>n</i> = 81) compared to a comparison group (<i>n</i> = 90) of healthy controls (HC). HRQoL was assessed with the RAND 36-item health survey, depressive symptoms were measured with the 21-item Beck Depression Inventory (BDI-II) and State/trait anxiety inventory (STAI) was used to estimate levels of state and trait anxiety. The hEDS group showed significantly lower scores on total HRQoL, on all subscales as well on calculated subgroups of physical and mental HRQoL than the HC group. Depression, state, and trait anxiety scores were significantly higher in hEDS group than in the HC group. However, both state and trait anxiety showed a lower degree of negative associations with social functioning in the hEDS group when compared to the HC group. Patients with hEDS present with a lower HRQoL and greater psychological distress than healthy individuals. These factors play a significant role in the patients’ overall functional capacity and should be noticed when examining and treating patients with hEDS.