Acute coronary artery occlusion triggers the release of atrial natriuretic peptide (ANP) from the heart. ANP affects vasodilation, natriuresis and inflammation, but the integrated biologic effects of ANP on myocardial infarction are unknown. To elucidate these effects, the left anterior coronary artery was ligated in anesthetized, ANP-deficient (ANP^-/-) and congenic wild-type (ANP^+/+) mice. The survival of ANP^-/- mice was markedly better (56%) 30 days post-infarction than the survival of ANP^+/+ mice (20%, p < 0.01). Surviving mice were comparable initially, but ANP^-/- mice developed more cardiac hypertrophy (p < 0.001) and had lower contractility indices 30 days after infarction (p < 0.05). Analysis 24 hours after coronary occlusion showed that ANP^-/- mice had smaller infarcts than ANP^+/+ mice (62.6% ± 12.1 vs. 100.8% ± 3.8, p<0.001) despite comparable areas at risk for ischemia. Administration of ANP to ANP^-/- mice via osmotic minipumps significantly enlarged infarct size to levels comparable to those observed in ANP^+/+ mice (p<0.05). There was no difference in neutrophil migration into the non-infarcted myocardium of ANP^-/- mice undergoing actual vs. sham coronary occlusion. By comparison, after coronary occlusion, the neutrophil infiltration into the myocardium was enhanced in ANP^+/+ mice (p < 0.0005) and ANP^-/- mice administered ANP (p < 0.0005). The expression of P-selectin, a molecule that mediates neutrophil adhesion, was significantly greater after coronary occlusion in the vasculature of ANP^+/+ mice or ANP^-/- mice treated with ANP, than in ANP^-/- mice (p< 0.002). Taken together, these results indicate that ANP increases P-selectin, neutrophil infiltration, infarct size and mortality following experimental coronary occlusion.