We measured the response to breathing a mixture of 80% helium and 20% oxygen (He) during a maximum expiratory flow-volume (MEFV) maneuver in 66 nonsmokers and 48 smokers, aged 17-67. All of the subjects studied had (forced expiratory volume in 1 s/forced vital capacity [FEV(1.0)/FVC]) x 100 of greater than 70%. While the flow rates of the smokers were within +/-2 SD of those of the nonsmokers at 50% VC (Vmax(50)), both groups showed a reduction in flow with age (nonsmokers: r=-0.34, P<0.01; smokers r=-0.52, P<0.001). Nonsmokers showed no significant reduction with age in response to breathing He, while smokers showed a marked reduction with age (r=-0.63, P<0.001 at Vmax(50)). We also measured the lung volume at which maximum expiratory flow (Vmax) while the subject was breathing He became equal to Vmax while he was breathing air, and expressed it as a percent of the VC. This was the most sensitive method of separating smokers from nonsmokers. These results indicate that the use of He during an MEFV maneuver affords sufficient sensitivity to enable detection of functional abnormalities in smokers at a stage when Vmax while they are breathing air is normal.