The objective of the study was to examine the burden of coronary artery disease (CAD) and heart failure (HF) on health-related quality of life (HRQOL) and the HRQOL trajectory among participants in a disease management (DM) program characterized by personalized models of education, counseling, and supportive contact. In all, 2,590 CAD and 3,182 HF patients were assessed at baseline and at 3, 6, 9, and 12 months post-enrollment. HRQOL was measured via a computerized dynamic test, whose core consisted of SF-8 items. HRQOL burden was assessed by comparing physical component summary (PCS) and mental component summary (MCS) scores to demographically adjusted US norms and to historical controls. Disease trajectories were assessed with change score analyses and by a categorization of participants as improving, stable, or deteriorating. Among the results, both groups showed between 1.7 to 2.6 times the likelihood of improving over worsening after a full year of DM participation in all measures. In contrast, historical controls experienced no significant HRQOL improvement or decline after 2 years of standard treatment. After 1 or 2 years they were more likely to decline than to improve in their PCS scores and were about as likely to improve as to worsen in their MCS scores. In conclusion, HF places a substantial burden on HRQOL, and the burden of CAD is also noticeable. While the study design does not allow causal interpretations, HRQOL significantly improved for both CAD and HF patients during DM program participation. This trend is in contrast to historic controls, where no significant HRQOL improvement occurred over time.