Objectives This study examined an anti-inflammatory property of high-density lipoprotein (HDL) in subjects with acute coronary syndrome (ACS) and stable coronary artery disease (CAD) compared with control subjects. Background HDL has anti-inflammatory properties in vitro, but its relationship to coronary disease in humans is unclear. The high-density lipoprotein inflammatory index (HII) measures the ability of HDL to mitigate oxidation of low-density lipoprotein; this function may be impaired in ACS and/or CAD. Methods We measured HII in 193 patients undergoing angiography for symptoms of CAD. Control subjects (n = 99) had no angiographic CAD, chronic CAD subjects (n = 51) had ≥70% vessel stenosis, and ACS subjects (n = 43) had ≥20% vessel stenosis and ischemia or infarction. We also examined HII in a cohort of healthy subjects randomly assigned to a statin or placebo. Results Subjects who had ACS had higher HII (less antioxidative capacity) compared with controls (1.57 vs. 1.17, p = 0.005) or those with chronic CAD (1.57 vs. 1.11, p = 0.006). HII was not different in subjects with stable CAD compared with controls. Furthermore, those subjects with higher HII were more likely to have ACS than no CAD (quartile 4 vs. 1, odds ratio OR: 1.74, p = 0.008). In a multivariate logistic regression model, HII was associated with ACS after adjusting for traditional cardiac risk factors (OR: 3.8, p = 0.003). There was a small improvement in HII after statin therapy compared with placebo (−14%, p = 0.03). Conclusions HDL has less anti-inflammatory capacity as assessed by HII in the setting of ACS compared with controls or subjects with chronic CAD.