We measured lung clearance of aerosolized technetium-labeled diethylenetriamine pentaacetic acid (99mTcDTPA) as an index of alveolar epithelial permeability in rabbits exposed to cigarette smoke. Eighteen rabbits were randomly assigned to 3 equal-size groups: control, all smoke exposure (ASE), and limited smoke exposure (LSE). Cigarette or sham smoke was delivered by syringe in a series of 5, 10, 20, and 30 tidal volume breaths with a 20-min counting period between each subset of breaths to determine 99mTcDTPA biologic half-life (T1/2). Mean T1/2 minimum (i.e., the smallest T1/2 observed) was significantly lower (p less than 0.05) for ASE and LSE rabbits than by control rabbits. We observed a significant difference at 20 and 30 breath exposures between the control and ASE group mean values (% baseline) for T1/2, arterial blood pressure, and peak airway pressure. A combination of light and electron microscopy showed focal alveolar edema and hemorrhage in the ASE and LSE groups but no alveolar-capillary membrane damage. In summary, acute cigarette smoke exposure increases alveolar permeability as measured by 99mTcDTPA clearance, but there was no detectable ultrastructural alteration of the alveolar-capillary membrane.