We tested the hypotheses that myocardial infarction in mice would lead to progressively worsening heart failure 12-18 weeks later and that exercise testing would provide a suitable means to evaluate left ventricular function sequentially. C57BL/6 mice (n = 69) underwent left coronary artery ligation (n = 50) or thoracotomy without ligation (n = 19). Sixteen animals (32%) died within 24 h of coronary ligation. Twenty additional animals (40%) died between days 3 and 14, and these mice showed infarct sizes of > 50% of the left ventricle. Fourteen animals (28%) that survived two weeks underwent echocardiography and treadmill testing 12 and 18 weeks after infarction, with no further mortality. Mice were then killed, morphometric assessment made, infarct size evaluated, and myocardial norepinephrine content and expression of BNP and ANF measured. Mice with infarcts >30% of the left ventricle (n = 6; 12% of original cohort) had left ventricular dilation (p < 0.0001) and hypertrophy (p < 0.001), impaired left ventricular systolic function (p < 0.0001) and reduced exercise duration (p = 0.03) and total work (p = 0.03) 12-18 weeks after infarction. Mice with infarcts <30% of the left ventricle (n = 8; 16% of original cohort) had no significant functional changes or left ventricular remodeling. Hearts from mice with infarcts > 30 % had reduced myocardial norepinephrine levels (MI <30%: 177+/-54 pg/mg, n = 6; MI >30%: 66+/-14 pg/mg wet weight, n = 4; p = 0.005) and increased mRNA content of BNP (p < 0.03) and ANF (p = 0.023). Coronary artery occlusion in mice provides a relevant model of clinical heart failure that is progressive and can be assessed by sequential exercise testing, providing a means to study the development of heart failure and its treatment.