Despite established exposure limits and safety standards, and the availability of carbon monoxide (CO) alarms, each year an estimated 50,000 people in the United States visit emergency departments for CO poisoning. Carbon monoxide poisoning can occur from brief exposures to high levels of CO or from longer exposures to lower levels. If the CO exposure is sufficiently high, unconsciousness and death occur quickly, and without symptoms. With non-lethal exposures to CO, common symptoms include headaches, nausea and vomiting, dizziness, general malaise, and altered mental status. Some patients may have chest pain, shortness of breath, and myocardial ischemia, and may require mechanical ventilation and treatment of shock. Individuals poisoned by CO often develop brain injury. As with brain injury from non- CO causes such as traumatic brain injury, the clinical expression of brain injury caused by CO poisoning includes the domains of cognition, affect, neurological, and somatic. Common problems are neurological: imbalance, motor weakness, neuropathies, hearing loss, tinnitus, Parkinson's-like syndrome, vestibular, gaze, auditory processing, cognitive, anxiety and depression, posttraumatic stress, personality change, persistent headaches, dizziness, sleep problems, and others. In addition, some will have cardiac or other problems. While breathing oxygen hastens the removal of carboxyhemoglobin (COHb), hyperbaric oxygen (HBO) hastens COHb elimination and favorably modulates inflammatory processes instigated by CO poisoning, an effect not observed with breathing normobaric oxygen. Hyperbaric oxygen improves mitochondrial function, inhibits lipid peroxidation transiently, impairs leukocyte adhesion to injured microvasculature, and reduces brain inflammation caused by CO-induced adduct formation of myelin basic protein. Based upon supportive randomized clinical trials in humans and considerable evidence from animal studies, HBO should be considered for all cases of acute symptomatic CO poisoning. Hyperbaric oxygen is indicated for CO poisoning complicated by cyanide poisoning, often concomitantly with smoke inhalation.