We have related the red cell mass (RCM) in 47 hypoxic patients with COPD (mean PO2, 52.5 +/- 5.2 SD mmHg; mean PCO2, 51.7 +/- 6.7 mmHg; mean/FEV1, 0.6 +/- 0.2 L; mean FVC, 1.7 +/- 0.6 L) to their smoking habits and outpatient carboxyhemoglobin concentrations. The mean RCM was 42.5 +/- 8.0 ml/kg in the 31 patients who still smoked, significantly (p less than 0.01) higher than in the 16 who were currently nonsmokers (RCM, 29.7 +/- 4.4 ml/kg). Measurements of arterial PO2, pH, P50, and COHb showed that the saturation of available hemoglobin (SO2A) was less well correlated (r = -0.36, p less than 0.05) with RCM in the smokers, than was SO2T (r = -0.58, p less than 0.001), SO2T including a corrective term for COHb. The RCM correlated well with the mean outpatient COHb measured repeatedly over 6 to 36 months in 40 of the patients but poorly with thier average arterial oxygen saturation (r = 0.15, p less than 0.1). In 15 patients given long-term oxygen therapy (15 hours/24-hour period) for 12 months RCM decreased significantly only in those who stopped smoking, as shown by a decrease in COHb. We conclude that cigarette smoking may determine the severity of secondary polycythemia in patients with hypoxic COPD, and prevent its correction by long-term oxygen therapy.