BACKGROUND: ApoB (apolipoprotein B)-containing lipoproteins are causal risk factors for atherosclerotic coronary artery disease (CAD). Since LL-37 (human cathelicidin peptide) binds to ApoB-100 in this pathological context, we investigated whether the circulating LL-37-ApoB-100 complex could serve as a biomarker for CAD. METHODS: We performed surface plasmon resonance and protein-protein docking to demonstrate the direct LL-37-ApoB-100 interaction. We developed a specific polyclonal antibody against the complex and measured its levels in human atherosclerotic plaques and plasma, as well as in Apoe(-/-) mice. An observational case-control study of 1103 patients undergoing coronary angiography from 2 independent centers assessed the association between LL-37-ApoB-100 and obstructive CAD. RESULTS: We identified that LL-37 directly interacted with multiple distinct binding sites on ApoB-100. Plasma levels of LL-37-ApoB-100 complex were significantly elevated in human patients with atherosclerosis. Consistently, levels of this complex were positively correlated with atherosclerotic plaque area in Apoe(-/-) mice. In the observational cohort from center 1, plasma LL-37-ApoB-100 levels were also significantly elevated in patients with obstructive CAD and strongly correlated with disease severity (Gensini score; r=0.60, P<0.001). Receiver operating characteristic curve analysis further demonstrated that LL-37-ApoB-100 was a valuable biomarker for the diagnosis of obstructive CAD, with an area under the curve of 0.82 (95% CIs, 0.81-0.85, P<0.001). After adjustment for lipid and clinical measures, elevated LL-37-ApoB-100 levels remained an independent predictor of obstructive CAD, with an adjusted odds ratio of 6.51 (95% CI, 4.34-9.77, P<0.001) for the upper quartiles. Observational analyses in center 2 showed consistent results. CONCLUSIONS: Circulating LL-37-ApoB-100 levels are strongly associated with angiographically documented CAD, highlighting LL-37-ApoB-100 as an independent predictor for CAD.