To investigate the influence of pulmonary emphysema and small airways abnormalities on ventilation-perfusion (VA/Q) mismatching in mild chronic obstructive pulmonary disease (COPD), we studied 23 patients (mean predicted FEV1, 76 +/- 15%) before lung resection because of a localized neoplasm. Respiratory gas exchange and VA/Q distributions were measured while the patients breathed room air and 100% O2. Breathing room air, the AaPO2 was moderately increased (25 +/- 12 mm Hg) as was VA/Q mismatching, indicated by the dispersion (log SD) of both blood flow (Q) and ventilation (V) distributions (log SD Q, 0.78 +/- 0.3; and log SD V, 0.66 +/- 0.28, respectively) (normal range, 0.3-0.6). AaPO2, log SD Q, and log SD V all significantly correlated with the emphysema severity assessed morphologically from the resected lung specimens (r = 0.57, r = 0.62, and r = 0.45, respectively). Log SD V also significantly correlated with the severity of the inflammatory infiltrate of membranous bronchioles (r = 0.62). During 100% O2 breathing there was an increase in VA/Q mismatching (log SD Q rose to 1.12 +/- 0.08, p less than 0.001), suggesting release of hypoxic pulmonary vasoconstriction. This increase in VA/Q inequality was not significantly related to the severity of lung pathologic findings. We conclude that, in mild COPD, both pulmonary emphysema and small airways abnormalities contribute to VA/Q mismatch, the severity of emphysema being the major morphologic correlate of the increase in AaPO2.