Patients with chronic obstructive pulmonary disease (COPD) present many neurological disorders of unknown origin. Although hypoxemia has long been thought to be responsible, several studies have shown evidence of neuronal damage and dysfunction even in non-hypoxemic patients with COPD. Adaptive mechanisms protect the brain from hypoxia: when arterial oxygen tension (PaO 2) decreases, the cerebral blood flow (CBF) increases, ensuring continuously adequate oxygen delivery to the brain. However, this mechanism is abolished during non-rapid eye movement (NREM) sleep. Any drop in PaO 2 during NREM sleep is therefore not compensated by increased CBF, causing decreased cerebral oxygen delivery with subsequent brain hypoxia. Patients with may therefore be exposed to neuronal damage during this critical time. This mechanism is of vital importance for patients with COPD because of the potentially deleterious cortical effects. Nocturnal desaturation is quite frequent in COPD and affects approximately one out of two patients who are not hypoxemic during wakefulness. Although the prevalence of NREM sleep desaturation has never been specifically assessed in COPD, current data suggest that at least half of the nocturnal desaturation in desaturating patients occurs during NREM sleep. This review presents the rationale for the hypothesis that nocturnal desaturation during NREM sleep promotes neuronal damage and dysfunction in COPD.