Patients with chronic severe lung disease are prone to develop pulmonary vascular remodeling, possibly through pulmonary endothelial dysfunction. Circulating endothelial progenitor cells (EPCs) are involved in maintenance of endothelial homeostasis. The aim of this study was to assess whether obstructive and restrictive lung diseases are associated with modification of EPC number in peripheral blood. The study was cross-sectional and involved patients with obstructive (n = 15) and restrictive (n = 15) lung disease on oxygen therapy and 15 control subjects. Circulating EPCs were defined by the surface expression of CD34, CD133, and kinase-insert domain receptor. Results from spirometric tests, blood gas analyses, and blood cell counts have been related to EPC numbers. Patients with chronic hypoxia and severe lung disease showed lower levels of all progenitors than do control subjects. A consensual further reduction of EPC was found in restrictive patients in comparison with obstructive patients. Among restrictive patients, EPC reduction was related to reduced lung volumes and impaired alveolo-arterial diffusion, whereas progenitor cell levels were directly related to erythrocyte number. Considering obstructive patients, significant correlations were found between progenitor cell levels and bronchial obstruction and between progenitor cell levels and arterial oxygen tension. These findings demonstrate a reduction of EPCs in patients with chronic lung disease and long-lasting hypoxia. This alteration was more evident in restrictive patients and correlated to disease severity. Depletion of circulating EPCs may be involved in altered endothelial homeostasis of pulmonary circulation in these disorders.