Airway permeability was examined in the 24-h period immediately after injury by cigarette smoke in 30 guinea pigs studied in groups of five at 30 min and 1, 6, 12, and 24 h after smoke exposure, and in 1 control group. The animals were anesthetized, tracheostomized, a carotid cannula inserted, and purified horseradish peroxidase was instilled on the airway surface via the tracheostomy tube. Blood samples (0.8 ml) were drawn and replaced with heparinized saline before and at 10, 15, 20, 30, and 40 min after horseradish peroxidase instillation. The animals were then killed, and samples of trachea and lung tissue taken for wet/dry wt determinations and for light and electron microscopic examination. The HRP concentrations in the blood were determined using an Elisa plate assay. We found the acute exposure to 100 puffs cigarette smoke resulted in a transient increase in airway epithelial permeability of HRP with a maximum at 30 min and a return to control values by 12 h after insult. These changes in mucosal permeability occurred in relation to a well-defined inflammatory reaction where increased permeability occurred during the exudative phase, which was monitored by measuring airway wet wt/dry wt ratios and the infiltration of polymorphonuclear cells. The return to the control value of permeability was associated with the repair phase of the inflammatory reaction, which was measured by monitoring basal cell mitoses.