Background: Several preliminary analyses suggested an association between neprilysin levels and myocardial infarction. Hypothesis: The objective was to assess whether Neprilysin (NEP) plasma levels following reperfusion might be a surrogate for infarct size (IS) or predict adverse outcomes in acute ST-segment elevation myocardial infarction (STEMI) patients. Methods: We measured NEP levels in a prospective cohort of 203 patients with STEMI referred for primary percutaneous coronary intervention. Circulating soluble NEP was measured by ELISA at admission (t0) and four hours later (t4) following reperfusion and on 7 times points (t0, t4, t12, t24, t48, day 7 and day 30) in a subset of 21 patients. Infarct size (IS) and left ejection fraction (LVEF) were measured at one month by cardiac magnetic resonance (CMR). Adverse cardiovascular outcomes were collected at 12-month follow-up. Results: Median t0 and t4 NEP levels in 203 patients were respectively 88.3 pg/mL (IQR [14; 375.4]) and 101.5 pg/mL (IQR [18.5; 423.8]). These levels remained unchanged over one month (p=0.70). NEP levels did not correlate significantly with IS (p=0.51) or LVEF (p=0.34). There was no correlation between NEP and troponin, creatine kinase and interleukin-6 levels at h0 and h4. NEP levels above the median were not associated with adverse outcomes at follow-up (HR= 1.28, 95%CI [0.69; 2.37]; p=0.42). Conclusions: NEP serum levels were widely distributed and did not change significantly in the first hours and one-month period following reperfusion in STEMI patients. There was no significant relationship with markers of infarct size and inflammation, and one-year adverse outcomes.