Repeated intermittent global hypoxia has been reported to markedly enhance hypoxic pulmonary vasoconstriction in dogs. We have reexamined this phenomenon but with intermittent unilateral alveolar hypoxia, avoiding complications of systemic hypoxemia. Fifteen anesthetized dogs were intubated with a double-lumen endotracheal tube, allowing separate ventilation of one lung with 100% N2 as a hypoxic challenge and the other lung with 100% O2 to maintain adequate systemic oxygenation. Distribution of lung perfusion was determined with intravenous 133Xe and external chest detectors. Each dog alternately breathed air or the unilateral alveolar hypoxia combination for 15 min each for a total of 12 hypoxic challenges or 6 h. Two groups emerged on the basis of the strength of their vasoconstrictor responses to successive hypoxic challenge. In group I (n = 6), perfusion to the hypoxic lung decreased 29% with the first challenge and decreased comparably with successive challenges. In group II, vasoconstriction was initially weak with perfusion decreasing only 5%, but perfusion decreased further with time alone (n = 5) or successive challenges (n = 4), falling 35% on the 12th challenge (comparable to group I). Delayed achievement of hypoxic vasoconstriction in group II may be secondary to a vasodilating prostanoid that disappears with time.