Nitrogen dioxide (NO₂) is a ubiquitous, pollutant gas that produces a broad range of pathological and physiological effects on the lung. Absorption of inhaled NO₂ is coupled to near-interfacial reactions between the solute gas and constituents of the airway and alveolar epithelial lining fluid. Although alveolar surfactant imparts limited resistance to respiratory gas exchange compared with that contributed by either the pulmonary membrane or uptake in red blood cells, resistance to NO₂ flux could have a significant effect on NO₂ absorption kinetics. To investigate the effect of interfacial surfactant on NO₂ absorption, we designed an apparatus permitting exposure of variably compressed monolayers. Our results suggest that compressed monolayers enriched in 1,2-dipalmitoyl-sn-3-glycero-phosphocholine present significant resistance to NO₂ absorption even at surface tensions greater than those achieved in vivo. However, monolayers composed of pure unsaturated phospholipids failed to alter NO₂ absorption significantly when compressed, in spite of similar reductions in surface tension. The results demonstrate that phospholipid monolayers appreciably limit NO₂ absorption and further that monolayer-induced resistance to NO₂ flux is related to physicochemical properties of the film itself rather than alterations within the aqueous and gas phases. On the basis of these findings, we propose that pulmonary surfactant may influence the intrapulmonary gas phase distribution of inhaled NO₂.