Objective: We hypothesized that elevated plasma YKL-40 levels are associated with increased risk of ischemic cardiovascular disease in the general population. In contrast to C-reactive protein (CRP) produced in the liver in response to inflammation, YKL-40 is produced by lipid-laden macrophages inside the vessel wall. Methods: We measured plasma YKL-40 in 8,899 21- to 93-year-old participants of the Copenhagen City Heart Study 1991-1994 examination, and followed them for up to 18 years. Endpoints were ischemic stroke, ischemic cerebrovascular disease, myocardial infarction, and ischemic heart disease. Hazard ratios were calculated for plasma YKL-40 levels in 10-year age percentile categories of 34 to 66%, 67 to 90%, and 91 to 100% versus 0 to 33%. Results: Multifactorially and CRP-adjusted hazard ratios for ischemic stroke were 1.2 (95% confidence interval, 0.9-1.6) for 33 to 66%, 1.8 (1.3-2.4) for 67 to 90%, and 2.3 (1.5-3.3) for 91 to 100% versus the 0 to 33% percentile category (p-trend <0.001). Corresponding hazard ratios for ischemic cerebrovascular disease were 1.2 (0.9-1.5), 1.6 (1.2-2.0), and 2.2 (1.6-3.2) (p-trend <0.001). Hazard ratios for myocardial infarction were not significant, whereas corresponding hazard ratios for ischemic heart disease were 1.0 (0.8-1.2), 1.2 (1.0-1.5), and 1.3 (1.0-1.6) (p-trend = 0.01). Stratifying for CRP or other risk factors gave similar results. A doubling in plasma YKL-40 was associated with multifactorially and CRP-adjusted increased risk of 20% (95% confidence interval, 11%-30%) for ischemic stroke, 16% (8%-24%) for ischemic cerebrovascular disease, 3% (-5%-11%) for myocardial infarction, and 7% (1%-12%) for ischemic heart disease. Interpretation: In the general population, elevated plasma YKL-40 levels are associated with increased risk of ischemic stroke and ischemic cerebrovascular disease, independent of plasma CRP levels. ANN NEUROL 2010;68:672-680