Abstract Background: Health-related quality of life and functional performance are important outcome measures following heart transplantation. This study investigates the impact of pre-transplant functional performance and post-transplant rejection episodes, obesity and osteopenia on post-transplant health-related quality of life and functional performance. Methods: Functional performance and health-related quality of life were measured in 70 adult heart transplant recipients. A composite health-related quality of life outcome measure was computed via principal component analysis. Iterative, multiple regression–based path analysis was used to develop an integrated model of variables that affect post-transplant functional performance and health-related quality of life. Results: Functional performance, as measured by the Karnofsky scale, improved markedly during the first 6 months post-transplant and was then sustained for up to 3 years. Rejection Grade ≥2 was negatively associated with health-related quality of life, measured by Short Form-36 and reversed Psychosocial Adjustment to Illness Scale scores. Patients with osteopenia had lower Short Form-36 physical scores and obese patients had lower functional performance. Path analysis demonstrated a negative direct effect of obesity (β = − 0.28, p < 0.05) on post-transplant functional performance. Post-transplant functional performance had a positive direct effect on the health-related quality of life composite score (β = 0.48, p < 0.001), and prior rejection episodes grade ≥2 had a negative direct effect on this measure (β = −0.29, p < 0.05). Conclusions: Either directly or through effects mediated by functional performance, moderate-to-severe rejection, obesity and osteopenia negatively impact health-related quality of life. These findings indicate that efforts should be made to devise immunosuppressive regimens that reduce the incidence of acute rejection, weight gain and osteopenia after heart transplantation. J Heart Lung Transplant 2003; 22:000–000.