The burden of obesity on patients' everyday life is high; obese subjects perceive a poor Health-Related Quality of Life (HRQL) in both physical and mental dimensions. We aimed to identify the areas of everyday life limited by health status and factors mainly responsible for perceived problems. The Nottingham Health Profile questionnaire (NHP) was used in 274 obese subjects seeking treatment at a university-based obesity center. Values were compared with normative Italian data, corrected for age and sex. Anthropometric and clinical data were also recorded, and correlated with health status. All domains of NHP were significantly impaired in obesity, the effect size ranging from 0.14 (Emotional Reactions; p = 0.02) to 0.99 (Physical Mobility; p < 0.0001), and varying in relation to gender, age and obesity class. Female subjects reported a higher-than-expected prevalence of problems in most areas of daily life [from 20% (Paid Employment) to 44% (Jobs around the home), compared with 14-26% in controls]. Males reported a high prevalence of problems in Sex life (31%), Holidays (37%) and Hobbies (49%), compared with 14, 14, and 16% in controls, respectively. Logistic regression analysis identified osteoarticular pain (knee and hip pain) and respiratory diseases as major factors predicting a poor HRQL in its physical dimensions, or perceived problems in everyday life. The relative importance of knee pain was higher than that of hip pain. Osteoarticular and respiratory diseases are major determinants of poor HRQL in obesity. Prevention strategies and treatment of somatic diseases are mandatory for a comprehensive approach to obesity.