Background: Generic and disease-specific health-related quality of life (HRQoL) questionnaires are commonly used in subjects with chronic obstructive pulmonary disease (COPD). However, it is not clear whether generic and disease-specific measures should be used in parallel, as they focus on different aspects of life. This study aimed to investigate the association between two most commonly used generic and disease specific HRQoL measures: Medical Outcomes Study Short Form 36- Item (SF-36) and St George's Respiratory Questionnaire (SGRQ). Materials and Methods: In a cross-sectional study, 58 subjects were selected through non-randomized systematic sampling from all COPD patients admitted to the "Respiratory Clinic of Baqiyatallah Hospital" during 2006. Each subject completed both SF-36 and SGRQ forms. Spirometry was also performed for each patient. The correlations between SGRQ total score and its subscores, including symptoms, activity and impacts, and SF-36 total score and its subscores, including physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role-emotional (RE) and mental health (MH), were assessed. Results: No significant correlation was found between the total score or subscores of SF-36 and the total score or subscales of SGRQ (p>0.05). Conclusion: The generic SF-36 and the disease specific SGRQ questionnaires assess different aspects of HRQoL in COPD patients and each should be used separately. The optimal approach appears to be the application of generic and disease-specific measures together, at least in the research setting. Further studies are recommended with larger sample size. (Tanaffos 2008; 7(2): 28-35)