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Abstract Background Neutrophil gelatinase-associated lipocalin (NGAL), a novel biomarker of acute kidney injury, might play a role in the development of atherosclerotic cardiovascular disease (CVD). We aimed to assess the association of circulating NGAL with CVD risk. Materials and methods Plasma NGAL concentrations were measured at baseline in 5275 participants in the PREVEND prospective study. Hazard ratios (95% confidence intervals [CI]) for CVD were estimated. Results After a median follow-up of 8.3 years, 338 participants developed first CVD events. Plasma NGAL was weakly to moderately correlated with several CVD risk markers. There was a non-linear relationship between NGAL and CVD risk. In analyses adjusted for established risk factors, the hazard ratio (95% CI) for CVD in a comparison of the top quartile versus bottom quartiles 1–2 of NGAL values was 1.35 (1.05–1.75; P = 0.022), which was abrogated after additional adjustment for other potential confounders (mainly attributed to high sensitivity C-reactive protein) 1.20 (0.92–1.57; P = 0.176). The association was considerably attenuated following further adjustment for renal function 1.05 (0.79–1.40; P = 0.745). The association between NGAL and CVD risk did not vary importantly in relevant clinical subgroups. Conclusion Evidence suggests a non-linear association between NGAL and CVD risk, which is dependent on inflammation and renal function. Highlights • Increased NGAL is associated with an increased CVD risk in Caucasians. • The association is non-linear and is independent of cardiovascular risk factors. • The association is partly dependent on inflammation and renal function. [ABSTRACT FROM AUTHOR]