Our laboratory has previously developed and validated a noninvasive soluble gas uptake method to measure airway blood flow (Qaw) in humans (Onorato DJ, Demirozu MC, Breitenbücher A, Atkins ND, Chediak AD, and Wanner A. Am J Respir Crit Care Med 149: 1132-1137, 1994; Scuri M, McCaskill V, Chediak AD, Abraham WM, and Wanner A. J Appl Physiol 79: 1386-1390, 1995). The method has the disadvantage of requiring eight breath-hold maneuvers for a single Qaw measurement, a complicated data analysis, and the inhalation of a potentially explosive gas mixture containing dimethylether (DME) and O2. Because of these shortcomings, the method thus far has not been used in other laboratories. We now simplified the method by having the subjects inhale 500 ml of a 10% DME-90% N2 gas mixture to fill the anatomical dead space, followed by a 5- or 15-s breath hold, and measuring the instantaneous DME and N2 concentrations and volume at the airway opening during the subsequent exhalation. From the difference in DME concentration in phase 1 of the expired N2 wash-in curve multiplied by the phase 1 dead space volume and divided by the mean DME concentration and the solubility coefficient for DME in tissue, Qaw can be calculated by using Fick's equation. We compared the new method to the validated old method in 10 healthy subjects and found mean +/- SE Qaw values of 34.6 +/- 2.3 and 34.6 +/- 2.8 microl.min(-1).ml(-1), respectively (r = 0.93; upper and lower 95% confidence limit +2.48 and -2.47). Using the new method, the mean coefficient of variation for two consecutive measurements was 4.4% (range 0-10.4%); inhalation of 1.2 mg albuterol caused a 53 +/- 14% increase in Qaw (P = 0.02) and inhalation of 2.4 mg methoxamine caused a 32 +/- 7% decrease in Qaw (P = 0.07). We conclude that the new method provides reliable values of and detects the expected changes in Qaw with vasoactive drugs. The simplicity and improved safety of the method should improve its acceptability for the noninvasive assessment of Qaw in clinical research.