Purpose: It is still unclear whether circulating levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) reflect cardiac filling and function in the critically ill patient, particularly during sepsis and a proinflammatory response that may induce NT-proBNP release from the heart. Materials and Methods: We prospectively evaluated the value of NT-proBNP as a marker of cardiac loading, function, and response to fluid loading in 18 septic and 68 nonseptic, critically ill patients in the intensive care unit of a university medical center. Transpulmonary thermal dilution and pressure measurements were done, and plasma NT-proBNP was determined before and after colloid fluid loading. Results: Compared with nonseptic patients, NT-proBNP plasma levels were higher and systolic cardiac function indices were lower in patients with sepsis than those without sepsis. N-terminal pro-B-type natriuretic peptide best related, from all hemodynamic parameters before and after fluid loading, to systolic cardiac function (rather than diastolic filling) variables, independently of confounders such as renal dysfunction (judged from serum creatinine). In addition, a high NT-proBNP (>3467 pg/mL) predicted absence of fluid responsiveness in sepsis only. Conclusions: Our data suggest that an increased circulating NT-proBNP plasma level is an independent marker of greater systolic cardiac dysfunction, irrespective of filling status, and is a better predictor of fluid nonresponsiveness in septic vs nonseptic, critically ill patients. © 2011 Elsevier Inc.