Background: although symptoms of heart failure abate after heart transplantation, other new symptoms caused by the surgery, immunosuppressant drugs, and complications can be new sources of symptom distress for patients after operation. Methods: This two-site national Institutes of Health study compared symptom distress in 173 adult heart transplant recipients from before operation to 3 months after operation. The Heart Transplant symptom scale was used to measure 92 symptoms related to heart disease and heart failure, transplantation, medication side effects, and complications commonly found in this population. Analysis was via paired t tests with Bonferroni correction. Most patients (93%) were receiving a triple immunosuppressant regimen of cyclosporine, azathioprine, and prednisone. Results: Total symptom distress decreased significantly (p = 0.013) from before operation to 3 months after heart transplantation. The 23 symptoms that decreased the most (p = 0.000) after operation accounted for a cumulative total reduction of 583% less symptom distress. These symptoms were primarily cardiopulmonary, neuromuscular, and emotional. The 10 symptoms that worsened the most (p = 0.000) after operation accounted for a cumulative total increase of 284% more symptom distress. These symptoms were primarily dermatologic, neurologic, and gastrointestinal and were all side effects of prednisone and cyclosporine. Conclusions: The net charge in symptom distress resulted in 299% less symptom distress in this cohort at 3 months after heart transplantation. This significant improvement in symptom outcomes scientifically documents the effectiveness of heart transplantation in reducing symptoms of heart failure, along with accompanying emotional symptoms. These research findings therefore reinforce and support the positive symptom outcomes often reported anecdotally in clinical practice.