In order to determine the initial values and dynamic changes of EPO (erythropoietin) after therapy, 57 consecutively presenting, typical COPD (chronic obstructive pulmonary disease) patients with chronic hypoxia and acute exacerbated serum EPO levels were serially measured. Initial mean EPO levels were slightly above the normal range (41.4±83.5 units/l), but in the majority of patients the initial EPO levels were significantly reduced. Following the correction of hypoxaemia, mean EPO levels decreased to 14.1±16.9 units/l ( P =0.0093). However, not all COPD patients showed this pattern; in an important subset of patients (36.8%), who had initially lower EPO levels and lower erythrocyte count, EPO levels were significantly increased (by more than 60%; P =0.0028) on the second day of treatment, despite correction of the hypoxaemia. This finding was unexpected and paradoxical when compared with physiological studies addressing the same issue. The data presented support previous reports of variable EPO levels in severely hypoxic COPD patients and suggest that the haematological response is already hampered at an early stage, at the level of EPO production, and much less likely at later steps in the haemopoietic response by failure to respond to elevated EPO levels. Our data are consistent with recent discoveries that the O 2 sensing and regulation of EPO production is a complex process in which multiple factors, including cytokines and therapeutic agents, play a role by enhancing or inhibiting the response. We believe that further studies on this clinical condition are complementary to basic physiological research and may help to elucidate the role of cytokines and other individual factors in complex clinical hypoxic situations.