Macrocytosis is a common finding in patients with chronic obstructive pulmonary disease (COPD). The cause for the elevation of mean corpuscular volume (MCV) in these patients remains elusive. In an attempt to determine the extent of macrocytosis in COPD patients and search for possible causative factors, we evaluated the hematologic parameters, F-cell percentage, blood gases and serum erythropoietin (Epo) Levels in 32 COPD clinically stable patients and 34 sex- and age-matched non-smoker healthy volunteers. An increased MCV was observed in almost half of the hypoxemic COPD cases (14/32 or 43.75%), while erythrocytosis developed to a lesser degree (37.5%). The erythropoietic response did not correlate with the severity of hypoxia. Moreover, no significant correlation was found between macrocytosis and hypoxemia or erythrocytosis and red cell size. In some cases the two phenomena occurred independently. The F-cell percentage was significantly elevated in the COPD group (P < 0.01) and was associated with MCV values (n = 32, r5 = 0.41, P < 0.05). This finding supports the hypothesis we put forward to explain the macrocytosis often observed in COPD, i.e., that the acute erythropoietic stress occurring repeatedly in these patients as a result of the frequent exacerbations may lead to waves of release of relatively immature, large red cells from the marrow, including an increased number of F-cells, reflecting the recruitment of normally dormant BFU-E (bursts forming units of erythrocyte precursors), which maintain the program for gamma-chain synthesis. The fact that erythrocytosis and macrocytosis, both being triggered by hypoxemia, do not occur consistently in all COPD patients indicates that many other factors may also intervene.