Background: Chronic obstructive pulmonary disease (COPD) patients enrolled into the Long-term Oxygen Treatment Trial had hypoxemia at rest, hypoxemia on exertion, or hypoxemia both at rest and on exertion. We hypothesized that patients with different patterns of hypoxemia may have significant differences in clinical features. Methods: All patients had COPD and oxygen saturation measured by pulse oximetry (blood oxygenation [SpO2]) at rest and during the 6-minute walk test (6MWT). Hypoxemia at rest was defined as resting SpO2 between 89-93%. SpO2<90% for at least 10 seconds and ≥80% for at least 5 minutes during ambulation characterized hypoxemia on exertion. Severe exercise hypoxemia (<80% for >1 minute) was exclusionary. Results: Of 738 patients studied, 133 (18.0%) had mild-moderate hypoxemia at rest only, 319 (43.2%) had hypoxemia on exertion only, and 286 (38.8%) had hypoxemia at both rest and exertion. Patients with hypoxemia at rest only were more likely to be current smokers, had higher body mass index (BMI) and a higher incidence of self-reported diabetes. Patients with hypoxemia on exertion only were more severely obstructed compared to the other groups. General and disease-specific quality of life scores were similarly impaired in all groups. Quality of well-being scores were more impaired in those with hypoxemia at rest only. Conclusions: COPD patients with mild-moderate hypoxemia have distinct clinical characteristics based on the pattern of oxygen desaturation at rest and with exertion.