Chronic exposure to hypercortisolism has significant impact on patient's health and health-related quality of life (HRQoL), as demonstrated with generic questionnaires. We have developed a disease-generated questionnaire to evaluate HRQoL in patients with Cushing's syndrome (CS; CushingQoL). Objective: Validate the CushingQoL questionnaire in patients with CS in clinical practice conditions. Design: Observational, international, cross-sectional study. Methods: A total of 125 patients were recruited by 14 investigators from Spain, France, Germany. The Netherlands, and Italy over a 2-month period. Clinical and hormonal data were collected and correlated with results of the generic short form 3 6 (SF-36) questionnaire, a question on self-perceived general health status and the CushingQoL score. Results: A total of 107 patients were pituitary-dependent and 18 adrenal-dependent CS; 104 (83%) were females, mean age 45 years (range 20-73 years); 39 (31%) were currently hypercortisolemic; and 47 (38%) adrenal insufficient. In clinical practice, CushingQoL was feasible (117; 94% of patients fully responded to the questionnaire in a mean time of 4 min), reliable (Crohnbach's α=0.87), and valid (factorial analysis demonstrated unidimensionality and Rasch analysis lead to a final version with 12 items). A significant (P<0.001) correlation was observed between CushingQoL score and patients self-perceived general health status and dimensions of SF-36 (Pearson's correlation coefficient ≥0.597). Patients with current hypercortisolism scored worse (lower) than those without (44±22 vs 56±21, P=0.004). Linear regression analysis identified female gender and hypercortisolism as significant predictors for worse QoL. Conclusion: CushingQoL is useful to evaluate HRQoL in patients with CS and correlates with clinical parameters. © 2008 Society of the European Journal of Endocrinology.