Solutions of 99mTc-diethylenetriaminepenta-acetate (99mTc-DTPA) and 99mTcO-4 were aerosolized and inhaled by subjects seated against a scintillation camera. Initial clearance rates of these radionuclides were determined over 6 posterior lung regions. Clearance of 99mTcO-4 (molecular weight, 163 dalton exceeded that of 99mTc-DTPA (molecular weight, 492 daltons) by an average factor of 3.3. Upper-lobe clearance of both radionuclides was greater than lower-lobe clearance in the normal subjects, but this gradient was abolished when the subjects exhaled against 7 cm of positive end-expiratory pressure. Twenty-one patients with clinical and roentgenographic evidence of interstitial lung disease (ILD) and diminished CO diffusion rates were studied with 99mTc-DTPA. Clearance of 99mTc-DTPA was increased in each of 5 patients with idiopathic pulmonary fibrosis, 4 of 8 with sarcoid, 2 of 5 with pneumoconiosis, and 2 of 3 patients with other forms of ILD. In contrast, the clearance of 99mTcO-4 was decreased in 4 patients with pulmonary alveolar proteinosis. Furthermore, no increase in 99mTc-DTPA clearance was found in 5 patients with chronic obstructive pulmonary disease. These studies suggest that the initial clearance of these aerosolized hydrophilic radionuclides is accomplished in part by diffusion through the epithelium of alveoli and respiratory bronchioles. Whereas radionuclide clearance is impaired by the presence of precipitated protein in these structures in pulmonary alveolar proteinosis, clearance is accelerated in ILD. This may indicate increased epithelial permeability in ILD related to injury and increased retractile forces.