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Background C-reactive protein (CRP), a marker of inflammation, and insulin resistance (IR), a metabolic disorder, are closely related. CRP and IR have both been identified as significant risk factors of cardiovascular disease (CVD) after adjustment for conventional CVD risk factors. It is not clear whether CRP predicts CVD independent of IR. Design Prospective population-based study. Methods Two thousand three hundred and fifty-seven Danish men and women, recruited from the general population, aged 41–72 years, without major CVD at baseline were studied. Traditional and new risk factors were recorded at baseline. CRP was determined by a high-sensitivity assay, and IR was determined by the homoeostasis model assessment (HOMA-IR) method. Results Over a median follow-up of 9.4 years, the incidence of the prespecified CV event, defined as the composite event of CV death, nonfatal ischaemic heart disease and nonfatal stroke, amounted to 222 cases. In Cox proportional-hazard models, adjusted for age, sex, smoking habit, total cholesterol, waist circumference, levels of triglycerides and high-density lipoprotein-cholesterol, systolic and diastolic blood pressures, physical activity and HOMA-IR, the hazard ratio (95% confidence interval) of a CV event was 1.33 (1.14–1.55; 0.001) per standard deviation increase in log-transformed CRP level. In the same model, the hazard ratio of a CV event was 1.11 (1.02–1.21; P < 0.05) per standard deviation increase in HOMA-IR level. Conclusion In a general Danish population free of major CVD at baseline, both CRP and IR were significantly related to risk of CVD.