Background Arginine vasopressin (AVP), produced by hypothalamic neurons, is released during stress following different stimuli such as hypotension, hypoxia, hyperosmolarity, acidosis, and infections. Measurement of AVP levels has limitations because of its short half-life and instability. Copeptin, the carboxy-terminal part of the precursor (prepro-AVP), is a more stable peptide and mirrors AVP concentrations. Aim The aim of this work was to study the usefulness of plasma copeptin as a predictor of prognosis and outcome of respiratory failure patients admitted in the ICU. Patients and methods This prospective study was carried out on 45 patients (38 patients admitted at Benha University Hospital ICU and Chest Department and seven healthy patients). They were classified into three groups: group A (ICU patients) comprised 30 patients admitted with respiratory failure due to different chest diseases; group B (inpatients) comprised eight patients selected from those hospitalized at Chest Department because of respiratory failure and with no need for ICU admission as a positive control group; and group C comprised seven healthy patients included as a negative control group. All patients were submitted to full clinical history and physical examination at ICU admission, as well as available preadmission clinical data, pulmonary function tests, chest radiography if done, arterial blood gases, ECG, and clinical lab data; blood samples were taken and plasma was separated and copeptin level was measured by sandwich immunoluminometric assay. Results There was a statistically significant difference among studied groups as regards plasma copeptin level, which was higher in ICU patients (group A) than in in-patients (group B) and healthy control patients (group C) (P