There have been recent indications that oxygen may nonspecifically oppose pulmonary vasoconstriction induced by a few vasoactive agents. Therefore, the authors examined the effect of 4 inspired oxygen tensions on the pulmonary vascular responses to exogenous prostaglandin F(2α) (PGF(2α)), serotonin (5-HT), 2-methylhistamine (2-MeH) (an H1-receptor agonist), histamine (after H2-receptor blockade with metiamide), and prostaglandin E1 (PGE1) in anesthetized dogs. An oxygen tension dependency on the pulmonary vascular responses to these vasoactive agents was observed, with each agent exhibiting maximal responses at different ranges of oxygen tension. PGF(2α) and PGE1 were most effective during hypoxia, while 5-HT, histamine, and 2-MeH produced maximal responses during normoxia. A comparison of dose-response curves for PGF(2α) during breathing of 2 inspired oxygen tensions indicated a decreased sensitivity, but not decreased reactivity, with the higher oxygen tension. The action of variable oxygen tensions on pulmonary vascular responsiveness to vasoactive agents suggests another role for oxygen in the control of the pulmonary circulation. It is not clear if oxygen acts nonspecifically on the vascular smooth muscle, or if it alters the metabolic mechanisms of vasoactive agent action.