The aim of this study was to determine health-related quality of life and fatigue measures in obese subjects and to compare scores with age- and gender-matched population norms. A total of 163 obese subjects were recruited from laparoscopic-adjustable gastric banding or exercise and diet weight loss programs between March 2006 and December 2007. All subjects completed the Medical Outcomes Study Short Form 36 (SF-36), Assessment of Quality of Life (AQoL), and Multidimensional Assessment of Fatigue (MAF) questionnaires. One-sample t-tests were used to compare transformed scores with age- and gender-matched population norms and controls. Obese subjects have significantly lower SF-36 physical and emotional component scores, significantly lower AQoL utility scores and significantly higher fatigue scores compared to age-matched population norms. Within the study cohort, the SF-36 physical functioning, role physical and bodily pain scores, and AQoL utility index were even lower in subjects with clinical knee osteoarthritis (OA). However, obese individuals without OA still had significantly lower scores compared to population norms. Obesity is associated with impaired health-related quality of life and disability as measured by the SF-36, AQoL, and fatigue score (MAF) compared to matched population norms.