Introduction: Multifactorial etiology of coronary artery disease (CAD) has been established in the recent studies. Extensive research is now underway to understand the mechanisms responsible for plaque vulnerability. The identification of a novel biomarker that will help in the assessment of plaque status is urgently needed for the purpose of patient stratification and prognostication. The aim of the present study was to evaluate leptin, pregnancy-associated plasma protein A (PAPP-A) and high sensitive C-reactive protein (hs-CRP) levels in patients with acute coronary syndrome and to assess their diagnostic efficacy in the identification of vulnerable plaques. Methods: The study group comprised 20 patients who had chest pain along with ECG changes (ST elevation, ST depression, T inversion) and raised cardiac enzyme levels. Twenty patients with chest pain and ECG changes but with normal cardiac enzyme profiles were included in the control group. Lipid profiles, and leptin, PAPP-A and CRP levels were assessed in these two groups. Box-Plot and Receiver operating characteristics (ROC) curves were plotted to determine the utility of the parameters under study as markers of plaque vulnerability. Results: Significantly higher levels of serum, leptin, PAPP-A and high-sensitivity CRP (hs-CRP) were observed in group 2 than in group 1. A positive correlation was observed between CRP and PAPP-A levels as well as CRP and leptin concentrations. ROC curve analysis revealed better efficacy of PAPP-A level over hs-CRP level in their ability to detect unstable plaques with areas under the curve of 0.919 for PAPP A versus 0.774 for hs-CRP, respectively. Conclusions: Our study highlights the utility of both CRP and PAPP-A levels as determinants of plaque instability. Our findings necessitate population-based follow-up studies to establish the superiority of either of the two biomarkers in the field of preventive cardiology.