Many patients suffering from obstructive sleep apnea (OSA) have intermittent oxygen desaturation associated with periods of apnea or hypopnea. Oxygen saturation levels below 90% are considered harmful. Usually, treatment is directed at correcting the apnea, which will in turn prevent hypoxemia. Unfortunately, many patients fail or are not candidates for nasal continuous positive airway pressure (CPAP) or surgical correction of their OSA. Forty-three patients with persistent OSA and nocturnal hypoxemia below 90% who were not candidates for additional surgical or CPAP therapy were treated with nocturnal oxygen supplementation. Standard symptoms associated with OSA and the Epworth Sleepiness Scale (ESS) were recorded before treatment and 30 days after the start of the treatment. In 21 patients, polysomnography studies were performed to compare the Respiratory Disturbance Index (RDI) score and minimum oxygen saturation levels when the patients were breathing room air or breathing 4 L/minute of oxygen by nasal cannula. Subjective symptoms of obstructive sleep apnea improved, and the ESS score significantly decreased after a 30-night treatment with oxygen. Split-night polysomnography showed a significant increase in minimum oxygen saturation during oxygen administration. The RDI did not significantly change with treatment. Oxygen administration for the correction of OSA-related nocturnal hypoxemia was both safe and effective in alleviation of OSA-related symptoms. It also appeared to have a beneficial effect on minimum oxygen saturation levels. Thus, oxygen therapy may be considered a treatment option in patients who fail to comply with CPAP and are not candidates for a surgical procedure.