To assess small airway disease in cystic fibrosis (CF) patients with minimal pulmonary involvement, maximal expiratory flow volume (MEFV) curves were obtained while the patients were breathing first air and then an 80% helium-20% oxygen gas mixture. Fifteen CF patients and 24 controls were studied. Flow rates at 50% and 25% vital capacity (VC) were calculated from the air and helium-mixture MEFV curves and were compared to give flow ratios at these lung volumes. At 50% VC, the helium/air flow ratios were similar in CF patients and normal subjects. At 25% VC, the flow ratio was significantly lower (p1/FVC, MMEF, RV/TLC, Vmax 50% TLC (TLC/see), and Vmax 25% VC (TLC/sec). Arterial oxygen tensions were below 86 mm Hg in four patients. Closing volumes by the 100% helium bolus technique were normal in all patients. Determination of the PIF appears to be a simple, noninvasive, and sensitive test for the detection of early small airway involvement.