Background: Radiation therapy to the mediastinum and breast can be associated with cardiac complications. Cardiac damage may manifest early during radiation therapy or occur late, years after radiation therapy has been finished. Hypothesis: Myocardial damage is associated with the release of both troponin I (TnI) and brain natriuretic peptide (BNP). The current study sought to determine whether radiation treatment to the mediastinum and breast leads to the release of cardiac biomarkers. Methods: The study comprised 23 patients: 18 with lung cancer and 5 with breast cancer. Radiation therapy was performed for up to 6 weeks. Total radiation dose was >45 Gy in each patient with a dose of 1.8 Gy per fraction. Blood samples to determine TnI and BNP were taken before and once a week during radiation therapy. Echocardiography was done before and after radiation had been finished. Results: Two patients died during the study. Both TnI and BNP levels increased significantly during the study (log₁₀ scale); however, absolute and mean values remained on a relatively low level (mean preradiation and postradiation TnI: 0.007 ± 0.008, 0.014 ± 0.01 ng/ml; mean preradiation and postradiation BNP: 123 ± 147, 159 ± 184 pg/ml). Conclusion: Radiation therapy leads to cardiac cell damage and changes in the left ventricular loading conditions as suggested by a significant increase of the cardiac biomarkers TnI and BNP. Determination of serum levels seems to be superior to echocardiography in detecting radiation-induced cardiac damage. Serial measurements of cardiac biomarkers may facilitate the management of patients undergoing radiation therapy and may help to define subgroups at high risk of developing heart failure.