Long-term facilitation (LTF) is a form of respiratory neuroplasticity frequently induced by acute intermittent isocapnic hypoxia (AIH, 3, 5-min isocapnic hypoxic episodes). Although repetitive apneas are a frequent natural occurrence producing brief (<30 sec) episodes of hypoxia and hypercapnia, it is unknown if repetitive apneas also elicit LTF. Apnea-induced LTF may preserve upper airway patency during sleep, thereby limiting further apneic events. We tested the hypothesis that repeated, brief ventilator-induced apneas are sufficient to induce serotonin-dependent phrenic and hypoglossal (XII) LTF in anesthetized rats. Anesthetized, male Sprague-Dawley rats were exposed to 3 or 6, 25-sec ventilator apneas with 5 min intervals, and compared to time control and AIH-treated rats. Three and six ventilator apneas induced phrenic and XII LTF with a magnitude similar to AIH. Both apnea-induced and AIH-induced LTF were associated with a decreased CO2 recruitment threshold for phrenic and XII activity (~4 mmHg). Spinal methysergide, a serotonin receptor antagonist, blocked apnea-induced LTF but not changes in the CO2-recruitment threshold. Thus brief ventilator apneas elicit phrenic and XII LTF. Similar to AIH-induced LTF, apnea-induced LTF is serotonin-dependent, and the relevant serotonin receptors for phrenic LTF are located in the cervical spinal cord. Clustered apneas during sleep may induce LTF as a form of compensatory plasticity, thereby preserving upper airway patency and adequate breathing during sleep. Thus, factors that diminish LTF may increase the incidence of obstructive sleep apnea.