Evidence is accumulating to support the presence of P2X purinergic receptors in the heart. However, the biological role of this receptor remains to be defined. The objectives here were to determine the role of cardiac P2X receptors in modulating the progression of post-myocardial infarction ischemic heart failure and to investigate the underlying mechanism. The P2X₄ receptor (P2X₄R) is an important subunit of native cardiac P2X receptors and cardiac-specific transgenic overexpression of P2X₄R (Tg) was developed as a model. Left anterior descending artery ligation resulted in similar infarct size between Tg and WT mice (P>0.1). However, Tg mice showed an enhanced cardiac contractile performance at 7 days, 1 month and 2 months after infarction and an increased survival at 1 and 2 months after infarction (P<0.01). The enhanced intact heart function was manifested by a greater global LV developed pressure and +dP/dt in vitro and by a significantly increased fractional shortening and systolic thickening in the non-infarcted region in vivo (P<0.05). The salutary effects on the ischemic heart failure phenotype were seen in both genders, and were not the result of any difference in infarct size in Tg vs. WT hearts. An enhanced contractile function of the non-infarcted area in the Tg heart was likely an important rescuing mechanism. The cardiac P2X receptor is a novel target to treat post-myocardial infarction ischemic heart failure.