Chronic hypoxemia is associated with development of secondary polycythemia. To evaluate effects of transient hypoxemia on serum EPO activity in patients with chronic lung disease, we studied six oxygen-dependent patients who underwent either a 4-h oxygen withdrawal or their routine therapy, in a randomized, blinded fashion, on two separate days. Serum EPO did not differ at baseline between study days. Erythropoietin levels did not change significantly over time during normoxic conditions. Under hypoxic conditions, serum EPO levels rose over 4 h with the change from baseline first becoming significant at 2 h. The log of serum EPO response showed an inverse correlation with the level of arterial oxygen saturation. We conclude that patients with chronic lung disease are able to produce EPO in response to acute hypoxemic stress. Transient episodes of hypoxemia, such as occur during sleep or exercise, may result in increased red blood cell production stimulated by this EPO response.