OBJECTIVE: We hypothesized a role for the inflammatory protein YKL-40 in atherogenesis and plaque destabilization based on its role in macrophage activation, tissue remodeling, and angiogenesis. METHODS: Serum YKL-40 levels were measured by enzyme immunoassay in 89 patients with carotid atherosclerosis and 20 healthy controls. Carotid expression of YKL-40 was examined by real time RT-PCR in 57 of the patients. Regulation and effect of YKL-40 were examined in THP-1 monocytes. RESULTS: Our main findings were: (1) serum YKL-40 levels were significantly elevated in patients with carotid atherosclerosis, with particularly high levels in those with symptomatic disease; (2) patients with recent ischemic symptoms (within 2 months) had higher YKL-40 mRNA levels in carotid plaque than other patients; (3) in vitro, the beta-adrenergic receptor agonist isoproterenol, toll-like receptor (TLR) 2 and TLR4 agonists, and in particular releasate from activated platelets significantly increased the expression of YKL-40 in THP-1 monocytes and (4) in vitro, YKL-40 increased matrix metalloproteinase-9 expression and activity in THP-1 monocytes, involving activation of p38 mitogen-activated protein kinase. CONCLUSIONS: Our findings suggest that YKL-40 might be a marker of plaque instability, potentially reflecting macrophage activation and matrix degradation within the atherosclerotic lesion.