Mice null for the gene encoding protein kinase C (Prkca), or mice treated with pharmacologic inhibitors of the PKC// isoforms, show an augmentation in cardiac contractility that appears to be cardioprotective. However, it remains uncertain if PKC itself functions in a myocyte autonomous manner to effect cardioprotection in vivo. Here we generated cardiac myocyte-specific transgenic mice using a tetracycline-inducible system to permit controlled expression of dominant negative (dn) PKC in the heart. Consistent with the proposed function of PKC, induction of dnPKCexpression in the adult heart enhanced baseline cardiac contractility. This increase in cardiac contractility was associated with a partial protection from long-term decompensation and secondary dilated cardiomyopathy following myocardial infarction (MI) injury. Similarly, Prkca null mice were also partially protected from infarction-induced heart failure, although the area of infarction injury was identical to controls. Thus, myocyte autonomous inhibition of PKC protects the adult heart from decompensation and dilated cardiomyopathy following infarction injury, in association with a primary enhancement in contractility.