Mice null for the gene encoding protein kinase Cα (Prkca), or mice treated with pharmacologic inhibitors of the PKCα/β/γ isoforms, show an augmentation in cardiac contractility that appears to be cardioprotective. However, it remains uncertain if PKCα itself functions in a myocyte autonomous manner to affect cardioprotection in vivo. Here we generated cardiac myocyte-specific transgenic mice using a tetracycline-inducible system to permit controlled expression of dominant negative PKCα in the heart. Consistent with the proposed function of PKCα, induction of dominant negative PKCα expression 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 after myocardial infarction 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 PKCα protects the adult heart from decompensation and dilated cardiomyopathy after infarction injury in association with a primary enhancement in contractility.