Our previous studies have shown that x-radiation produces cardiac lesions. Likewise, adriamycin, a useful antineoplastic agent, is known to be cardiotoxic. Maximal "safe" doses have been established for each of these forms of therapy. Since combined therapy with adriamycin and radiation is being used for malignancies involving the mediastinum, it is important to know whether the combination of both agents is more cardiotoxic than either agent alone. In this study young New Zealand White rabbits were divided into five groups and given: (1) a single dose of x-radiation of 1600 rads in the cardiac area; (2) 167 mg. per sq. m. of adriamycin; (3) both raddiation and adriamycin at the same doses; (4) 255 mg. per sq. m. of adriamycin; (5) no treatment. Animals in the third (combined) group developed radiation and adriamycin lesions, the frequency and severity of which were greater than those in the single therapy groups at the same (low) doses. These observations suggest a synergistic effect of the two agents. If so, patients receiving combined treatment are at risk of developing severe carditis from doses of adriamycin and cardiac x-radiation today regarded as safe. Although neither one is specific, the light and electron microscopic lesions caused by x-radiation (myocardial capillary damage, pericarditis) were easily distinguished from those caused by adriamycin (myocyte damage). Both agents led to diffuse myocardial fibrosis. These morphologic characteristics may have clinical applications.