Digoxin-like immunoreactive factor (DLIF) is an endogenous substance with natriuretic and diuretic activity. Elevated plasma levels of DLIF are found in various clinical states characterized by water and sodium retention. Chronic respiratory failure, particularly of an advanced stage, also is frequently associated with water and sodium retention. In order to determine whether elevated plasma levels of DLIF are present in chronic respiratory failure, we measured plasma DLIF levels in seven patients (four with COPD [two of whom had associated sleep apnea disturbance] and three with kyphoscoliosis) suffering from advanced chronic respiratory failure with severe hypoxemia and hypercapnia. We found that in these patients plasma levels of DLIF were significantly higher than in healthy control subjects. We conclude that patients with advanced chronic respiratory failure respond with increased levels of DLIF. This may represent an attempt at homeostasis of water and sodium metabolism which is frequently deranged in this clinical condition.