The acute phase of isoproterenol cardiotoxicity in the rat heart was studied by both scanning and transmission electron microscopy. The endocardium and immediate adjacent myocardium of the left ventricle and septum were chosen for examination because this area should be less affected by myocardial underperfusion. The initial damage, which was mainly to the endocardium, was well defined by 30 minutes; this damage consisted of endocardial cell contraction and separation with activated platelets adhering to the exposed subendocardium. Myocardial cell changes were present at 1 hour and always included those cells adjacent to the endocardium; frequently the damage did not extend to involve the deeper tissue layers. Polymorphonuclear leukocytes were present but not in large numbers before three hours. These results suggest that myocardial ischemia due to the action of isoproterenol is not a major factor in isoproterenol cardiotoxicity.