A key role has been proposed for reactive oxygen species (ROS) in chronic obstructive pulmonary disease (COPD). Aim of the present work was to evaluate possible implications of ROS in the integrity and function of the cell type mainly involved in oxygen uptake and delivery to the peripheral tissues: the erythrocyte. Red blood cells (RBCs) were thus collected from blood samples from COPD patients. Furthermore, blood samples from the same patients treated with the anti-oxidizing drug of widespread use in such disease i.e., N-acetylcysteine (NAC), were also considered. Morphometric and analytical cytology studies were then conducted. We report herein that: (i) alterations of RBC ultrastructure were detectable in RBCs from COPD patients, that (ii) relevant changes of spectrin cytoskeleton and glycophorin expression were also found and that (iii) NAC treatment was capable of significantly counteracting these changes. These results are consistent with a reappraisal of the role of RBCs in this disease.