Purpose: Multi-attribute utility instruments (MAUIs) are widely used to measure utility weights. This study sought to compare utility weights of two popular MAUIs, the EQ-5D-3L and the SF-6D, and inform researchers in the selection of generic MAUI for use with cardiovascular (CVD) patients. Methods: Data were collected in the Young@Heart study, a randomised controlled trial of a nurse-led multidisciplinary home-based intervention compared to standard usual care. Participants (n = 598) completed the EQ-5D-3L and the SF-12v2, from which the SF-6D can be constructed, at baseline and at 24-month follow-up. This study examined discrimination, responsiveness, correlation and differences across the two instruments. Results: Both MAUIs were able to discriminate between the NYHA severity classes and recorded similar changes between the two time points although only SF-6D differences were significant. Correlations between the dimensions of the two MAUIs were low. There were significant differences between the two instruments in mild conditions but they were similar in severe conditions. Substantial ceiling and floor effects were observed. Conclusions: Our findings indicate that the EQ-5D and the SF-6D cover different spaces in health due to their classification systems. Both measures were capable of discriminating between severity groups and responsive to quality of life changes in the follow-up. It is recommended to use the EQ-5D-3L in severe and the SF-6D in mild CVD conditions.