Functional magnetic resonance imaging was used to map cerebral activation in 16 patients with obstructive sleep-disordered breathing (OSDB) and 16 healthy subjects, during the performance of a 2-back verbal working memory task. Six patients with OSDB were reimaged after a minimum period of 8 wk of treatment with positive airway pressure. Working memory speed in OSDB was significantly slower than in healthy subjects, and a group average map showed absence of dorsolateral prefrontal activation, regardless of nocturnal hypoxia. After treatment, resolution of subjective sleepiness contrasted with no significant change in behavioral performance, persistent lack of prefrontal activation, and partial recovery of posterior parietal activation. These findings suggest that working memory may be impaired in OSDB and that this impairment is associated with disproportionate impairment of function in the dorsolateral prefrontal cortex. Nocturnal hypoxia may not be a necessary determinant of cognitive dysfunction, and sleep fragmentation may be sufficient. There may be dissociations between respiratory vs. cortical recovery and objective vs. subjective recovery. Hypofrontality may provide a plausible biological mechanism for a clinical overlap with disorders of mood and attention.