OBJECTIVES To examine the impact of obesity on health-related quality of life (HRQOL) in patients with asthma. METHODS The data used for the present study was obtained from the 2004-2006 Medical Expenditure Panel Survey (MEPS) data, a comprehensive national representative survey of the U.S. non-institutionalized population. Individuals were included if they were aged 18-74, self report of diagnosed with asthma or diagnosed with ICD-9 code of 493 by their physician, and did not have pregnancy, malignancy, kidney dialysis, or immunodeficiency. Asthma patients were classified as normal (body mass index(BMI):18.5-<25), or obese(BMI:≥30). MEPS measured HRQOL using SF-12 physical component scale (PCS-12), SF-12 mental component scale (MCS-12), Kessler Index (K-6), and Patient Health Questionnaire (PHQ2). The K-6 assesses the person's non-specific psychological distress (higher value means severe mental disability) and the PHQ2 assesses the depression severity. PHQ2 score of ≥3 was used to screen asthma patient with depression. The impact of obesity on HRQOL was estimated using multivariable regression while controlling for patients' demographic, socio-economic, and co-morbidity variables. Data were analyzed using SAS and STATA. RESULTS A total of 5339 asthma patients were identified. Overall, HRQOL in obese patients were significantly lower compared to those of normal weight patients (50.7 vs. 41.9 for PCS-12, 49.0 vs. 47.0 for MCS-12, 3.9 vs. 5.3 for K-6, 0.6 vs. 1.1 for PHQ-2). While controlling for the study variables, QOL were worse if patients were obese, older, female, or less educated, as well as have cardiovascular disease. Proportion of patients with PHQ2 score ≥3 were 10.3% in normal weight and 19.7% in obese patients. CONCLUSIONS Obesity significantly deteriorates quality of life including both physical and mental components in asthma patients. The national health promotion to control weight needs to be emphasized to increase the beneficial effects of HRQL in asthma patients.