BACKGROUND: The concurrent comparison of questionnaires assessing health-related quality of life in the same population is necessary for better appreciating their performance and to select the best instrument for a given purpose (e.g. clinical trials and observational studies). AIM: The aim of this study was to compare the measurement properties of two disease-specific and generic questionnaires: the Obesity-related Well-Being (ORWELL97), the Obesity-Related Disability test (TSD-OC), the EuroQoL, and the World Health Organization Quality of Life questionnaire. MATERIALS/SUBJECTS: Two-hundreds and forty-nine obese inpatients [age 47 (standard deviation, SD 15) years, body mass index 44.4 (SD 5.2) kg/m(2), 69 % female] completed the four questionnaires before and after a 3-week multidisciplinary weight reduction program. Standard measurement properties were calculated and compared. RESULTS: Intra-class correlation coefficient ranged from 0.73 to 0.90 for most of the instruments and subscales. The standard error of measurement ranged from 9 to 21 % for the generic instruments, and from 9 to 44 % for the specific questionnaires. Missing data and ceiling effects were found for TSD-OC. Responsiveness was similar for all the instruments. The correlations between the change scores of the instruments were small (<0.37). CONCLUSIONS: It was not possible to identify a "best" instrument, but overall the ORWELL97 seems to show better measurement properties. The two specific instruments measured different constructs and they did not show a clear superior performance compared to the generic questionnaires.