Gas exchange was investigated in normal anesthetized dogs during high-frequency, low-tidal volume ventilation (HFV) using the multiple inert gas elimination method. The pattern of inert gas elimination was initially normal during conventional mechanical ventilation. During hFV there was an increase in the difference between the excretion values of acetone and its less soluble neighboring gases, enflurane and ether, but elimination was independent of molecular weight. This pattern was consistent with a major degree of parallel ventilation-perfusion inequality with 49.4 ± 1.7 % of alveolar ventilation being distributed to lung units with V̇A/Q ratios >20. Additional experiments, however, showed insufficient change in pulmonary blood flow distribution during HFV to account for these apparently poorly perfused lung units. Instead, it was found that the flux from the lung of the most soluble gas, acetone, per unit concentration difference along the airways was approximately twice that for other gases. Experiments using a simple airway model suggested that this enhanced transport of high-solubility gases during HFV is dependent on the wet luminal surface of conducting airways. A reciprocating exchange of gas between the lumen and airway lining layer is proposed as the most likely explanation for these results.