We studied the effect of positive pressure mechanical ventilation on the pulmonary clearance (k) of99mtechnetium diethylenetriamine pentaacetate (99mTc- DTPA) in lambs. Twelve lambs were anesthetized and ventilated with air at 25 breaths/min and with end expiratory airway pressure at 2 cm H2O for a minimum period of 8 h. Four lambs received normal pressure ventilation with peak airway pressure at 17 ± 3 cm H2O and eight received high pressure ventilation with peak airway pressure at 41 ± 2 cm H2O. Three99mTc-DTPA clearance studies were done in each lamb; at the start and after 4 and 8 h of mechanical ventilation. All clearance measurements were made at normal peak airway pressure 16 ± 3 cm H2O. Baseline clearance rate, k, (n=12) was 1.2 ± 0.5% (SD). During normal pressure ventilation, k increased from 1.0 ± 0.5 to 2.2 ± 0.8% after 4 h and to 2.7 ± 0.8% after 8 h. During high pressure ventilation, k increased from 1.4 ± 0.4 to 3.6 ± 1.3% after 4 h and to 4.8 ± 1.2% after 8 h. To see if 8 h of mechanical ventilation was associated with other evidence of lung epithelial injury, we determined the movement of I125labeled albumin from the interstitium into the airspace, lung water content, lung histology, and lung lavage constituents in the lambs at the end of the study. All variables were similar between ventilated and four unventilated lambs, except the percentage of alveolar macrophages recovered by lavage, which was more in the ventilated lambs. We conclude that positive pressure mechanical ventilation results in a continuous increase in the pulmonary clearance of99mTc-DTPA and the duration and magnitude of positive pressure applied tended to increase the value of k.