Background: Vascular calcification has been found to be associated with increased risk of cardiovascular (CV) morbidity and mortality. Various bone-associated proteins have been suggested to be related with this process. In this study, we aimed to evaluate whether serum levels of bone morphogenic protein-4 (BMP-4) and matrix Gla protein (MGP) differed in patients who were found to have normal epicardial coronary arteries or a culprit lesion in the coronary angiography leading to acute coronary syndrome (ACS). Methods: Patients admitted to emergency department with the diagnosis of ACS who underwent primary percutaneous coronary intervention (PCI) between October 2015 and April 2016 were consecutively recruited as the patient group. Age and gender-matched subjects who underwent coronary angiography following non-invasive ischemia assessment made the control group. Results: A total of 90 subjects (63.00±14.02 years, 70% male) were included in this study. MGP (<0.001) and BMP-4 (<0.001) levels were significantly elevated when compared to subjects with normal coronary arteries. Fasting blood glucose (P=.024), HDL-cholesterol (P=.002), C-reactive protein (CRP) (P=.001) levels, and left ventricular ejection fraction (LVEF) (P=.021) were significantly correlated with serum MGP levels. HDL-cholesterol (P=.001) and CRP (P=.030) levels were also significantly correlated with serum BMP-4 levels. In the model including HDL-cholesterol, CRP, MGP, and BMP-4 levels, only MGP (odds ratio[OR]: 1.018, P=.019) and BMP-4 (OR: 1.313, P=.023) were found to be independently associated with ACS. Conclusion: This study shows that serum BMP-4 and MGP are independently associated with ACS occurrence when adjusted for other CV risk factors. These biomarkers may have a diagnostic potential in ACS patients.