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Objectives: Impaired nitric oxide (NO) bioavailability may contribute to microvascular dysfunction in sepsis. Excessive plasma NO consumption has been attributed to scavenging by circulating cell-free hemoglobin. This may be a mechanism for NO deficiency in sepsis and critical illness. We hypothesized that plasma NO consumption is high in critically ill patients, particularly those with sepsis, acute respiratory distress syndrome (ARDS), shock, and in hospital nonsurvivors. We further hypothesized that plasma NO consumption is correlated with plasma cell-free hemoglobin concentration., Design: Retrospective cohort study., Setting: Adult ICUs of an academic medical center., Patients and Subjects: Three hundred sixty-two critically ill patients and 46 healthy control subjects., Interventions: None., Measurements and Main Results: Plasma NO consumption was measured using reductive chemiluminescence and cell-free hemoglobin was measured with a colorimetric assay. Mean (95% CI) plasma NO consumption (µM) was higher in critically ill patients versus healthy control subjects (3.9 [3.7-4.1] vs 2.1 [1.8-2.5]), septic versus nonseptic patients (4.1 [3.8-4.3] vs 3.6 [3.3-3.8]), ARDS versus non-ARDS patients (4.4 [4.0-4.9] vs 3.7 [3.6-3.9]), shock vs nonshock patients (4.4 [4.0-4.8] vs 3.6 [3.4-3.8]), and hospital nonsurvivors versus survivors (5.3 [4.4-6.4] vs 3.7 [3.6-3.9]). These relationships remained significant in multivariable analyses. Plasma cell-free hemoglobin was weakly correlated with plasma NO consumption., Conclusions: Plasma NO consumption is elevated in critically ill patients and independently associated with sepsis, ARDS, shock, and hospital death. These data suggest that excessive intravascular NO scavenging characterizes sepsis and adverse outcomes of critical illness., Competing Interests: Ms. Rovitelli’s institutions received funding from the University of Rochester School of Medicine and Dentistry and the National Heart, Lung, and Blood Institute (NHLBI). Ms. Rovitelli, Dr. Storms, and Dr. Pietropaoli received support for article research from the National Institutes of Health. Dr. Wexler’s institution received funding from the American Heart Association. Dr. Pietropaoli’s institution received funding from the American Heart Association (13CRP17110114). Dr. Pietropaoli was supported by the Scientific Advisory Committee Incubator Program of the University of Rochester School of Medicine and Dentistry. Dr. Pietropaoli, Ms. Rovitelli, and Ms. Mroczek are supported by the NHLBI of the National Institutes of Health under award number R01 HL 160723. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)