We have investigated a new technique that could be specific for detecting small airway diseases. We measured resistance in nine subjects, evaluating the effect of breathing 80% He-20%O2, air, and 80% SF6-20% O2 at different flow rates (0.25--1.01 l/s) and frequencies (4--12 Hz). To test the sensitivity and specificity of this new technique, we used intravenous histamine infusion to cause peripheral constriction. During histamine infusion six of nine subjects showed the following changes: 1) dynamic compliance decreased; 2) subjects developed frequency dependence of compliance, and 3) there was no significant change in pulmonary resistance or Rrs (respiratory resistance) at 4 Hz. These data suggested a time-constant discrepancy in the periphery due to histamine infusion. These six subjects also developed frequency dependence of resistance (delta Rrs from 4 to 12 Hz), which was significant when breathing air (-22 +/- 6%) and maximal when we used He-O2 (-32 +/- 3%). We conclude that He-O2 can improve the specificity of frequency dependence of Rrs for detecting events occurring in the peripheral airways.