BACKGROUND: Severe hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD). Long-term oxygen therapy is beneficial in hypoxemic COPD patients. However, the clinical and radiographic predictors of hypoxemia and the use of oxygen therapy are not well described. This study aimed to find the correlates of resting hypoxemia and the pattern of oxygen use in moderate to severe COPD patients. METHODS: Subjects with GOLD stage II or higher COPD from the first 2500 COPDGene subjects were included in this analysis. All subjects were current or ex-smokers between ages 45 and 80. Severe resting hypoxemia was defined as room air oxygen saturation (SpO(2)) =88%. Use of supplemental oxygen therapy was determined by questionnaire. RESULTS: Eighty-two of 1060 COPD subjects (7.7%) had severe resting hypoxemia. Twenty-one of the 82 (25.6%) were not using continuous supplemental oxygen. Female sex, higher BMI, lower FEV(1), and enrollment in Denver were independent risk factors for hypoxemia; emphysema severity on quantitative chest CT scan did not predict hypoxemia. 132 of 971(13.6%) subjects without severe resting hypoxemia were using continuous supplemental oxygen. In non-hypoxemic oxygen users, Denver recruitment, higher BMI, lower FEV(1), and more severe dyspnea were associated with the use of continuous oxygen. CONCLUSIONS: A large number of COPD patients without severe hypoxemia were using supplemental oxygen therapy and the pattern of oxygen use was affected by factors other than resting SpO(2) and emphysema severity. Longitudinal data will be required to reveal the effects of oxygen therapy in this subgroup. Clinical trial registration: http://clinicaltrials.gov (NCT00608764).