Long-term facilitation (LTF) of breathing elicited by episodic hypoxia (EH) is an extensively studied example of plasticity of respiratory motor behavior. Previous studies employed the paradigm of EH wherein each episode of hypoxia was 5 min. This paradigm is rarely encountered in nature. Brief episodes of hypoxia are encountered frequently with recurrent apneas, wherein hypoxic episodes last a few seconds only. Recent studies suggest that chronic intermittent hypoxia (CIH) represents a form of oxidative stress involving reactive O2species. The objectives of the present study were to determine 1) whether acute, repeated, brief EH (15 s) elicit LTF in breathing and 2) whether prior conditioning with CIH modulates acute EH-induced LTF of breathing, and if so whether reactive O2 species are involved. Experiments were performed on anesthetized, vagotomized, paralyzed, and mechanically ventilated rats, and efferent phrenic nerve activity was monitored as an index of respiratory motor output. In control animals, acute EH (15-s hypoxia; 10 episodes; n = 9) increased minute neural respiration, which persisted during 60 min of the posthypoxic period, suggesting LTF of breathing. EH-induced LTF of respiration was markedly augmented in CIH-conditioned animals (15-s hypoxia, 9 episodes/h, 8 h/day for 10 days; n = 9). By contrast, conditioning with a comparable, cumulative duration of sustained hypoxia (4-h hypoxia; n = 8) did not augment LTF elicited by acute EH. Systemic administration of manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (5 mg · kg−1 · day−1for 10 days), a potent scavenger of O[Formula: see text]·, prevented CIH-induced potentiation of LTF ( n = 9). These results demonstrate that 1) acute, brief EH elicits LTF in respiratory motor output; 2) prior conditioning with CIH, but not with comparable, cumulative duration of sustained hypoxia, augments LTF elicited by acute EH; and 3) O[Formula: see text]· radical scavenger prevents CIH-induced potentiation of LTF of respiration.