Induction of myocardial necrosis by isoproterenol produces resistance to the necrogenic effects of subsequent doses of the drug. A series of experiments were performed to further define the determinants of resistance. Myocardial necrosis was induced in male Sprague-Dawley rats by sc injection of isoproterenol at 50 micrograms/kg daily for 10 consecutive days or as a single dose at 50, 5, or 0.5 micrograms/kg. These preconditioning doses were followed, at various times, by a challenge dose of 50 micrograms/kg. The rats were killed 48 hr after the challenge dose, and their hearts were analyzed morphometrically to determine the amount of acute necrosis and scarring. The amount of scar tissue was a reflection of necrosis caused by the preconditioning dose whereas acute necrosis reflected response to the challenge dose. Resistance occurred and lasted longer than 19 to 20 weeks after both single or multiple isoproterenol injections of 50 micrograms/kg, but it was not observed 5 days after administration of a single preconditioning dose. Isoproterenol at 0.5 micrograms/kg produced only very minimal or no myocardial necrosis and did not produce resistance. The resistance was not dependent on the size of the area of necrosis produced during the preconditioning period, showing that it was not due to destruction of all vulnerable muscle by the preconditioning dose(s). The preexistence of lesions, however, was necessary for the development of resistance. It is concluded that development of resistance to the necrogenic effects of isoproterenol reflects an adaptive alteration in the myocardium which survives after a necrogenic dose.