Chronic obstructive pulmonary disease (COPD) is characterized by a decline in FEV₁ and, in many advanced patients, by arterial hypoxemia with or without hypercapnia. Spirometric and gas exchange abnormalities have not been found to relate closely, but this may reflect a narrow range of severity in patients studied. Therefore, we assessed the relationship between pulmonary gas exchange and airflow limitation in patients with COPD across the entire severity spectrum. Ventilation-perfusion mismatch (V_A/Q) was measured using the multiple inert gas elimination technique in 150 patients from previously published studies. The distribution of patients according to the GOLD stage of COPD was: 15 with stage 1; 40 with stage 2; 32 with stage 3; and 63 with stage 4. In GOLD stage 1, AaPO₂ and V_A/Q mismatch were clearly abnormal; thereafter, hypoxemia, AaPO₂ and V_A/Q imbalance increased, but the changes from GOLD stages 1 to 4 were modest. Post-bronchodilator FEV₁ was related to PaO₂ (r = 0.62) and PaCO₂ (r = - 0.59) and to overall V_A/Q heterogeneity (r = - 0.48) (p < 0.001 each). Pulmonary gas exchange abnormalities in COPD are related to FEV₁ across the spectrum of severity. V_A/Q imbalance is disproportionately greater than airflow limitation in GOLD stage 1, suggesting that COPD initially involves the smallest airways, parenchyma and pulmonary vessels with minimal spirometric disturbances. That progression of V_A/Q inequality with spirometric severity is modest may reflect pathogenic processes that reduce both local ventilation and blood flow in the same regions through airway and alveolar disease and capillary involvement.