OBJECTIVES:  Recently, a health related quality of life comorbidity index (HRQoL-CI) was developed to risk adjust SF-12 Physical Component Score (PCS) and Mental Component Score (MCS). HRQoL-CI, however, does not include gender-specific diseases. This study aimed to evaluate the performance of existing HRQoL-CI across gender and if required, revise HRQoL-CI with gender-specific measures. METHODS: Using Medical expenditure Panel Survey (MEPS) 2003, the performance of HRQoL-CI was assessed in overall population, and in population stratified by gender, for adults ≥18 years of age. All the analysis was done using cluster-specific Self-administered Questionnaire weights. The Least Square Absolute Shrinkage and Selection Operator (LASSO), with a partition fraction of 0.25, was used to identify best gender-specific predictors for PCS and MCS. Results compared using graphical diagnostic plots. RESULTS: The overall population included an estimated sample of 102.71million males and 110.63million females. Bivariate t-test showed gender was statistically significantly different for PCS (p<0.001) and MCS (p<0.001).  After including age, race and HRQoL-CI, the gender was not statistically significantly different for PCS (p=0.5266) but was for MCS (p<0.0001). However, model performance varied across males and females compared to overall sample. For PCS, R2=0.3055 for overall population, 0.3306 among females and 0.2761 among males; for MCS, R2=0.1269 for overall population, 0.1341 among females and 0.1108 among males.  In comparison to 20 diseases in HRQoL-CI, the LASSO analysis gave 6 best predictor for females (R2=0.2814) and 2 for males (R2=0.1591) for PCS. For MCS, it identified 2 best predictors for males and females (R2=0.0823), in comparison to 15 diseases in HRQoL-CI. Inclusion of gender-specific diseases did not improve the model performance. CONCLUSIONS: The study suggests that extent of risk adjustment for HRQoL varies across gender and the contribution of the gender-specific variables was minimal for risk adjustment purposes.