Background <p>Serum Angiopoietin-2 (Ang2) is a novel indicator of vascular inflammation that has demonstrated predictive potential in multiple studies. However, the association between Ang2 and the presence of layered plaques (LP) in patients with acute coronary syndrome (ACS) has not been well-established. The aim of the present study was to investigate the observational association of serum levels of Ang2 with LP by optical coherence tomography (OCT).</p> Methods <p>This study was a retrospective observational study. A total of 101 consecutive ACS patients who transferred from the emergency department to the cardiology department were included, mainly patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI). Preoperative OCT images were collected from all patients. According to the presence or absence of LP in the target lesion, the patients were divided into the LP group (<i>n</i> = 38) and the non-layered plaque (NLP) group (<i>n</i> = 63). The concentration of Ang2 was measured by enzyme-linked immunosorbent assay (ELISA). The binary logistic regression model was used to assess the relationship between Ang2 and LP, and the receiver operating characteristic (ROC) curve was used to evaluate the ability of Ang2 to discriminate LP in ACS lesions. Information about Ang2 was obtained through online databases and literature review.</p> Results <p>There was a significant difference in Ang2 concentration between the LP group and the NLP group (18.97&#xa0;ng/mL, 95% CI 15.25–22.12 vs 14.79&#xa0;ng/mL, 95% CI 12.13–20.28, <i>p</i> = 0.023). Univariate and multivariate analyses indicated that serum Ang2 was significantly associated with the presence of LP. For every 1-unit increase in Ang2 concentration, there was a 16.7% increase in the odds of LP (OR = 1.167, 95% CI 1.051–1.295, <i>p</i> = 0.004). Ang2 was divided into quartiles. With the increase of Ang2 quartile level, the incidence of LP also showed an upward trend. This is consistent with the results of multivariate analysis of Ang2 quartiles, indicating that elevated Ang2 levels are significantly correlated with higher odds of LP. At the same time, the ROC curve showed that the area under the curve (AUC) of Ang2 for discriminating LP was 0.635 (95% CI 0.523–0.748, <i>p</i> = 0.023), and the optimal cutoff value was 15.045&#xa0;ng/mL (sensitivity of 0.789 and specificity of 0.556). When combined with DBP, HR, admission events, dyslipidemia, smoking history, hs-CRP and Mechanical Circulatory Support (MCS), the AUC increased to 0.735 (95% CI 0.634–0.835, <i>p</i> = 0.0001).</p> Conclusions <p>This study found that Ang2 was significantly associated with LP, which provides a preliminary clue for future prospective studies to verify its potential clinical relevance, and the prevalence of LP increases with the increase of Ang2 quartile level. These observational findings are hypothesis-generating and need to be further validated in mechanism studies and prospective studies.</p>