OBJECTIVES:  Comorbidities in Heart Failure (HF) patients are highly prevalent, adversely affecting health related quality of life (HRQoL). Health related quality of life-comorbidity index (HRQoL-CI) has been recently developed to risk adjust HRQoL. The aim of this study was to compare the performance of HRQoL-CI with Charlson and Elixhauser measures in predicting HRQoL in HF patients. METHODS:  The Medical Expenditure Panel Survey  2002-2008 data was used for this retrospective cross-sectional study. All adults (age >18 years) diagnosed with HF were included in the study. International Classification of Disease, 9th Revision, Clinical Modification and Clinical Classification Codes were used to identify HF patients, as well as to construct different risk adjustment measures (D’hoore adaptation of Charlson, Elixhauser and HRQoL-CI). HRQoL is documented in MEPS using short form health survey (SF-12), with physical component score (PCS) and mental component score (MCS). Linear regression analysis was conducted with PCS and MCS scores as dependent variables. Age, race and sex were included as baseline variables in all models while incorporating Charlson/D’hoore, Elixhauser, and HRQoL- CI measures one at a time. Adjusted R2 were compared to assess the comparative performances of risk-adjustment measures. RESULTS:  The mean age was 68±13 years, with 80.63% non-Hispanic whites. The average PCS and MCS for HF patients were 45.53±12.28 and 30.64±11, respectively. HRQoL-CI (R2 = 0.2083) outperformed Elixhauser (R2 = 0.1784) and Charlson/D’hoore (R2 = 0.1359) in predicting PCS. Whereas, Elixhauser (R2 = 0.2184) had the best prediction of MCS compared to HRQoL-CI (R2 = 0.1920) and Charlson/D’hoore (R2 = 0.0918). CONCLUSIONS:  No single comorbidity measure was best in predicting both PCS and MCS in HF patients; HRQoL-CI performed best in predicting PCS whereas Elixhauser measure had the best prediction for MCS. Selection of risk adjustment method should be based on the type of dimension used to evaluate HRQoL.