The exchange characteristics of a highly soluble gas with the pulmonary airways during a single-exhalation maneuver were analyzed using a mathematical model previously described by our group (M. E. Tsu et al. Ann. Biomed. Eng. 16: 547-571, 1988). The model integrates the simultaneous exchange of water, heat, and a soluble gas with the pulmonary airways. The purpose of this paper is to provide experimental data for model validation. Exhaled ethyl alcohol concentration profiles of human subjects were measured with an Intoxilyzer 5000 and were plotted against exhaled volume measured with a wedge spirometer. Each subject performed a series of breathing maneuvers in which exhalation flow rate was the only variable. Phase III has a positive slope (0.047 +/- 0.0089 mol alcohol in air.mol alcohol in alveolus-1.l-1) that is statistically independent (P > 0.05) of flow rate. Reducing the molecular diffusion coefficient of alcohol in the nonperfused tissue layer improves the fit of the model to the experimental data. The optimal diffusion coefficient of alcohol for all subjects was 12 +/- 5.3 (SD) x 10(-7) cm2/s, which is 8% of the diffusion coefficient of alcohol in water (1.6 x 10(-5) cm2/s). We concluded that the experimental data showing a positive slope of the exhaled alcohol profile are consistent with a reduced diffusivity of alcohol in the respiratory mucosa. The reduced diffusion coefficient enhances reabsorption of alcohol by the airways on exhalation and creates a positive phase III slope.