<b><i>Background and Aim:</i></b> Neutrophil gelatinase-associated lipocalin (NGAL) is derived from the distal tubule and is both reabsorbed and filtered and also shed into the urine after tubular injury. Plasma NGAL is unique amongst the candidate biomarkers of acute kidney injury (AKI) since elevated concentrations may reflect either a change in renal glomerular function or in structural tubular injury or both. In this study, we compared the performance of plasma NGAL in the diagnosis of functional changes and in the diagnosis of structural injury. <b><i>Methods:</i></b> Plasma and urine samples from 528 patients were collected on entry to an intensive care unit (ICU) as well as 12 and 24 h later. Plasma NGAL diagnostic performance was independently assessed for Functional-AKI and Structural-AKI. Functional-AKI was defined by changes in plasma creatinine, whereas Structural-AKI was defined by elevations in urinary NGAL. <b><i>Results:</i></b> On ICU entry, the area under the curve (AUC) for the diagnosis of Functional-AKI was 0.74 (95% CI: 0.69-0.79), and for Structural-AKI it was 0.79 (0.74-0.83). Plasma NGAL also predicted the need for dialysis (0.79; 0.66-0.81), but not for death. A principal component analysis demonstrated that the maximum plasma NGAL in 24 h reflected structural injury marginally more than functional changes. Plasma NGAL added value to an AKI diagnostic model comprising plasma creatinine, sepsis, age, and APACHE II score (integrated discrimination improvement: 0.073; 0.034-0.12). <b><i>Conclusion:</i></b> Increased plasma NGAL reflects both decreased filtration and structural injury. For patients at a low calculated risk, the addition of NGAL reduced the risk, and for those at a higher risk, NGAL correctly assigned patients to even a higher risk.