OBJECTIVE:Measurement of health-related quality of life (HRQoL) is a crucial aspect of cost-effectiveness analysis. Two of the most widely used instruments for assessing HRQoL are EQ-5D and SF-6D. Previous studies have shown that the sensitivity of these instruments differ depending on the severity of the disease.  However, few studies have systematically compared EQ-5D and SF-6D scores in a representative sample of the general population. The objective of this study is to describe and compare HRQoL derived from EQ-5D and SF-6D in a Swedish general population for age, gender and seven disease groups (respiratory, tumor, endocrine, cardiovascular, orthopedic, mental and rheumatic diseases). METHODS: The EQ-5D and SF-6D were included in a cross-sectional postal health survey in Östergötland County to a representative sample (n=6628, age: 18–84). RESULTS: When comparing EQ-5D and SF-6D with regard to age,  the mean HRQoL with EQ-5D  across all ages was 0.81, ranging from 0.86 (18-29 years) to 0.71 (80-84 years). For SF-6D mean HRQoL for the same population was 0.74, ranging from 0.75 (18-29 years) to 0.66 (80-84 years). With regard to gender, HRQoL was higher overall for men compared to women.  Men had an EQ-5D score of 0.83 and a SF-6D score of 0.79 in contrast women had an EQ-5D score of 0.79 and a SF-6D score of 0.73. Across disease groups the mean EQ-5D scores ranged from 0.60 (rheumatic) to 0.75 (endocrine), mean SF-6D index values ranged from 0.64 (rheumatic) to 0.71 (endocrine). CONCLUSION: Although EQ-5D and SF-6D appear to measure similar constructs our results show that HRQoL varies greatly among the general population depending on chosen instrument. However, when comparing our results across disease groups, differences between the instruments appear less substantial. Our findings could have serious implications for the transparency of cost-effectiveness analysis, if different studies use HRQoL measurements that are not equivalent.