Six patients, ages 29–58 yr, were investigated during barbiturate and fentanyl anesthesia. After intubation with a double-lumen bronchial catheter, one lung was ventilated continuously with 100% O2, and the other was rendered hypoxic during three 15-min periods by ventilation with 95% N2+ 5% O2, with intervening 15-min periods of oxygen ventilation. Cardiac output was determined by thermodilution, and the distribution of blood flow between the lungs was assessed from the excretion of a continuously infused poorly soluble gas (SF6). The first hypoxic challenge resulted in a 10% increase in cardiac output (QT) and a reduction in the fractional perfusion of the test lung from 57% to 31% of QT. The pulmonary artery mean pressure increased by 54%, and the vascular resistance of the test lung increased threefold. The venous admixture increased from 19% to 40% of QT, whereas the inert gas shunt remained unaltered at 15% (inert gases also being eliminated by nitrogen-ventilated areas). The arterial oxygen tension decreased from 353 mmHg to 79 mmHg. On resumption of the control state, central hemodynamics and gas exchange returned to the initial values. The second and third hypoxic challenges resulted in reductions in the fractional perfusion of the test lung to 35% and 37% of QT. All other variables were altered to the same degree as during the first challenge. The authors conclude that hypoxic challenge of one lung in an intravenously anesthetized human subject elicits a maximum vasoconstrictor response within the first 15 min, and this response cannot be potentiated by repeated challenges.