To help define the mechanisms involved in the handling of propranolol by normal and injured lungs, we studied the pulmonary extraction of [3H]propranolol in 23 unanesthetized sheep. Extraction of propranolol by normal lungs during a single circulation was characterized by 1) subsequent back-diffusion and pulmonary retention of the drug, 2) no evidence of saturable uptake or binding, 3) no effect of isoproterenol or imipramine, and 4) no effect of increasing cardiac output by treadmill exercise. In lungs damaged by oxygen toxicity, [3H]propranolol extraction decreased progressively to 63% of base line, paralleling progressive arterial hypoxemia and hypercapnia. In contrast, [14C]serotonin extraction remained unchanged from base line. Our results suggest that in normal unanesthetized sheep, pulmonary extraction of propranolol occurs primarily by passive diffusion that is flow-limited. Also, lung injury induced by oxygen toxicity in sheep reduces the pulmonary extraction of propranolol. Indeed, in oxygen toxicity, the depressed extraction of propranolol is a more sensitive marker of lung injury than is serotonin extraction.