Chronic obstructive pulmonary disease (COPD) is characterized by a decline in forced expiratory volume in 1 s (FEV(1)) 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 severity spectrum. Ventilation-perfusion (V(A)/Q) mismatch was measured using the multiple inert gas elimination technique in 150 patients from previous 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, AaPo(2) and V(A)/Q mismatch were clearly abnormal; thereafter, hypoxemia, AaPo(2), and V(A)/Q imbalance increased, but the changes from GOLD stages 1-4 were modest. Postbronchodilator FEV(1) was related to Pa(O(2)) (r = 0.62) and Pa(CO(2)) (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 FEV(1) across the spectrum of severity. V(A)/Q imbalance, predominantly perfusion heterogeneity, 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.