Purpose: The purpose of this study was to evaluate the relationship between apolipoprotein A-IV (apoA-IV) plasma concentrations and acute coronary syndrome (ACS). Methods: Plasma apoA-IV concentrations were measured in 115 patients with different types of ACS and in 68 gender- and age-matched control subjects using Enzyme-Linked Immunosorbent Assay (ELISA) kits. The clinical data were collected by an internist, who was blinded to plasma apoA-IV concentrations. Results: Plasma apoA-IV levels in ACS patients were significantly decreased compared to the levels in control subjects (437.0 ± 157.5 μg/mL vs. 590.2 ± 183.7 μg/mL, P < 0.001). An statistically significant decreasing trend of plasma apoA-IV levels from the control subjects, to patients with unstable angina pectoris (UAP) (457.3 ± 152.9 μg/mL), to patients with acute myocardial infarction (AMI) (311.7 ± 127.8 μg/mL), was observed. Moreover, plasma apoA-IV level was negatively associated with New York Heart Association (NYHA) functional class. NYHA class II (467.2 ± 142.1 μg/mL, P < 0.001) and class III/IV (368.1 ± 170.8 μg/mL, P < 0.001) patients had statistically decreased levels of plasma apoA-IV when compared to the control subjects. A stepwise multivariate regression analysis identified types of ACS, NYHA classes, and plasma fibrinogen levels as the most important determinants of plasma apoA-IV levels in ACS patients. Conclusions: Low plasma apoA-IV levels are associated with ACS, and plasma apoA-IV levels may be a potential treatment target for ACS patients.