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This study assessed the ability of a brief, well-validated generic health-related quality of life (HRQOL) measure to characterize the symptom burden of patients with irritable bowel syndrome (IBS) with reference to a large survey of U.S. community-living adults.One hundred four Rome II diagnosed patients with IBS completed measures of pain, psychological dysfunction (neuroticism, somatization, distress, abuse), and HRQOL (SF-36, IBS-QOL, CDC HRQOL-4) during baseline assessment of a National Institutes of Health-funded clinical trial. The four-item CDC HRQOL-4 assesses global health and the number of days in the past 30 days resulting from poor physical health, poor mental health, and activity limitation.Patients with IBS averaged 15 of 30 days with poor physical or mental health. These average overall unhealthy days exceeded those of respondents with arthritis, diabetes, heart disease/stroke, cancer, and class III obesity (body mass index ≥40 kg/m2) from the U.S. survey. Fifteen percent of patients identified musculoskeletal disorders, not IBS symptoms, as the major cause of their activity limitation. Overall unhealthy days among patients with IBS varied directly with IBS symptom severity, abuse, pain, and psychological distress. Controlling for personality variables that influence perception and reporting HRQOL did not diminish the statistical significance of associations between the CDC HRQOL-4 and other study measures.The CDC HRQOL-4 is a psychometrically sound, rapid, and efficient instrument whose HRQOL profile reflects the symptom burden of moderate-to-severe IBS, is sensitive to treatment effects associated with cognitive behavior therapy, and is not a proxy for personality variables identified as potential confounders of HRQOL. HRQOL is related to but not redundant with psychological distress.