Angiotensin-converting enzyme 2 (ACE2) cleaves Angiotensin-II to Angiotensin-(1-7), a cardioprotective peptide. Serum soluble ACE2 (sACE2) activity is raised in chronic heart failure, suggesting a compensatory role in left ventricular dysfunction. Our aim was to study the relationship between sACE2 activity, infarct size, left ventricular systolic function and remodeling following ST-elevation myocardial infarction (STEMI). A contrast-enhanced cardiac magnetic resonance study was performed acutely in 95 patients with first STEMI and repeated at 6 months to measure LV end-diastolic volume index, ejection fraction and infarct size. Baseline sACE2 activities, measured by fluorescent enzymatic assay 24 to 48 hours and at 7 days from admission, were compared to that obtained in 22 matched controls. Patients showed higher sACE2 at baseline than controls (104.4 [87.4-134.8] vs 74.9 [62.8-87.5] RFU/µl/hr, p<0.001). At seven days, sACE2 activity significantly increased from baseline (115.5 [92.9-168.6] RFU/µl/hr, p<0.01). An inverse correlation between sACE2 activity with acute and follow-up ejection fraction was observed (r = −0.519, p<0.001; r = −0.453, p = 0.001, respectively). Additionally, sACE2 directly correlated with infarct size (r = 0.373, p<0.001). Both, infarct size (β = −0.470 [95%CI:−0.691:−0.248], p<0.001) and sACE2 at 7 days (β = −0.025 [95%CI:−0.048:−0.002], p = 0.030) were independent predictors of follow-up ejection fraction. Patients with sACE2 in the upper tertile had a 4.4 fold increase in the incidence of adverse left ventricular remodeling (95% confidence interval: 1.3 to 15.2, p = 0.027). In conclusion, serum sACE2 activity rises in relation to infarct size, left ventricular systolic dysfunction and is associated with the occurrence of left ventricular remodeling.