Aim <p>The objective was to assess the clinical efficacy of long non-coding RNA (lncRNA) alpha-2-macroglobulin-antisense 1 (A2M-AS1) in acute myocardial infarction (AMI).</p> Methods <p>One hundred patients with AMI and eighty patients with chest pain were recruited in the case-control study. A2M-AS1 expression was examined by quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) analysis was utilized for evaluating the diagnostic value. Pearson’s correlation analysis was used to analyze the correlation between A2M-AS1 and conventional AMI biomarkers. AMI-associated risk indicators were identified using logistic regression analysis.</p> Results <p>A significant reduction of serum A2M-AS1 was measured in AMI patients relative to chest pain patients. A2M-AS1 had an area under the curve (AUC) of 0.927 to distinguish AMI patients from those with chest pain. Pearson’s correlation analysis showed that A2M-AS1 was adversely correlated with white blood cell (WBC) (<i>r</i>=-0.6682, <i>P</i> &lt; 0.001), low density lipoprotein cholesterol (LDL-C) (<i>r</i>=-0.5795, <i>P</i> &lt; 0.001), creatine kinase MB (CK-MB) (<i>r</i>=-0.6022, <i>P</i> &lt; 0.001) and cTnl (<i>r</i>=-0.5473; <i>P</i> &lt; 0.001), while positively correlated with high density lipoprotein cholesterol (HDL-C) (<i>r</i> = 0.6445, <i>P</i> &lt; 0.001). Relative to non-Major Adverse Cardiovascular Events (non-MACE) group, serum A2M-AS1 was obviously declined in the MACE group of AMI patients with high capacity to distinguish the MACE group from the non-MACE patients (AUC = 0.802). Additionally, A2M-AS1 (<i>P</i> = 0.013; OR = 0.268; 95%CI = 0.095–0.760) was a risk indicator for predicting MACE with AMI patients, as well as age (<i>P</i> = 0.014; OR = 3.478; 95%CI = 1.285–9.414).</p> Conclusion <p>A reduction in A2M-AS1 expression was observed in AMI patients, suggesting its potential as an underlying indicator for AMI diagnosis.</p>