Several members of secreted frizzled-related protein (SFRP) are involved in the process of myocardial ischemia-reperfusion injury. However, little is known about the role of SFRP5 in patients with acute ST-segment elevation myocardial infarction (STEMI). In this cross-sectional study, 85 patients with first-time anterior STEMI who underwent timely primary percutaneous coronary intervention (PCI) and 35 patients without coronary artery disease (CAD) were enrolled. Serum SFRP5 levels were measured using an enzyme-linked immunosorbent assay kit. Patients with STEMI were divided into low-SFRP5 and high-SFRP5 groups according to their median baseline serum SFRP5 levels. To evaluate cardiac function and structure after infarction, the left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume (LVEDV) were measured using echocardiography. The associations between changes in LVEF and reduced LVEF (≤ 50%) and clinical variables were determined by univariate and multivariate analyses. Baseline serum SFRP5 levels were significantly higher in patients with STEMI than in those without CAD (23.3 ng/mL vs 19.8 ng/mL, P=0.008), although they decreased over time. Also, baseline serum SFRP5 levels were inversely correlated with peak hypersensitive cardiac troponin I (hs-cTnI) levels (r=-0.234, P=0.025) and peak hypersensitive C-reactive protein (hs-CRP) levels (r=-0.262, P=0.015). A multivariate linear regression model showed that changes in LVEF were positively correlated with serum SFRP5 levels at baseline (β= 0.249, 95% confidence interval (CI) 0.018-0.245, P=0.024) and 24 h after admission (β=0.220, 95% CI 0.003-0.264, P=0.045). At 3 months, LVEF in patients with high SFRP5 levels was significantly improved over baseline [(60.8±7.1) % vs (56.1±7.5) %, P=0.001]. LVEF was also significantly higher in patients with high SFRP5 levels than in those with low at the 3-month follow-up [(60.8±7.1) % vs (56.8±8.9) %, P=0.028]. Consequently, high serum SFRP5 levels at baseline were associated with a decreased risk of reduced LVEF at 3 months, independent of peak hs-cTnI and baseline cardiac function (hazard ratio 0.190, 95% CI 0.036-0.996; P=0.049). High serum SFRP5 levels measured during the acute phase of STEMI were significantly associated with promoting myocardial recovery at an early phase following primary PCI, suggesting that SFRP5 is a potential therapeutic target in acute STEMI.