Abstract Purpose Health-related quality of life (HRQOL) can be significantly impaired by the presence of chronic conditions such as cardiovascular disease (CVD) and major depressive disorder (MDD). The aim of this paper was to (1) identify differences in HRQOL between individuals with CVD, MDD, or both, compared to a healthy reference group, (2) establish whether the influence of co-morbid MDD and CVD on HRQOL is additive or synergistic and (3) determine the way in which depression severity interacts with CVD to influence overall HRQOL. Methods Population-based data from the 2007 Australian National Survey of Mental Health and Well-being (NSMHWB) (n = 8841) were used to compare HRQOL of individuals with MDD and CVD, MDD but not CVD, CVD but not MDD, with a healthy reference group. HRQOL was measured using the Assessment of Quality of Life (AQOL). MDD was identified using the Composite International Diagnostic Interview (CIDI 3.0). Results Of all four groups, individuals with co-morbid CVD and depression reported the greatest deficits in AQOL utility scores (Coef: -0.32, 95 CI: -0.40, -0.23), after adjusting for covariates. Those with MDD only (Coef: -0.27, 95 CI: -0.30, -0.24) and CVD only (Coef: -0.08, 95 CI: -0.11, -0.05) also reported reduced AQOL utility scores. Second, the influence of MDD and CVD on HRQOL was shown to be additive, rather than synergistic. Third, a significant dose?response relationship was observed between depression severity and HRQOL. However, CVD and depression severity appeared to act independently of each other in impacting HRQOL. Conclusions HRQOL is greatly impaired in individuals with co-morbid MDD and CVD; these conditions appear to influence HRQOL in an additive fashion. HRQOL alters with depression severity, therefore treating depression and improving HRQOL is of clinical importance.