Objectives: For patients admitted with an acute exacerbation of COPD (AECOPD) and a need for supplementary oxygen therapy, to determine if peripheral oxygen saturation < 88% (hypoxemia) or >92% (hyperoxemia), within first 24 hours of admission, is associated with ‘treatment failure’ or fewer days alive and out of hospital within 14 days after admission. Design: A retrospective multicenter observational study, reviewing consecutive data on SpO2, oxygen, and drug administration at three predefined time points, on adverse events in patients admitted with COPD between December 2019 and June 2020. Multivariable logistic regression analysis, Mann Whitney U- and Chi-square-test were used. Setting: Acute hospital setting, across four different hospitals in the capital region of Denmark. Participants: Patients with a confirmed diagnosis of COPD admitted with an acute exacerbation and an oxygen need within the first 24 hours admission. Results: In total 289 COPD patients were included. The median age was 74.8 years [interquartile range (IQR):69.6 to 81.8], 191 were female and 132 patients experienced ‘treatment failure’. A minimum of one episode of hypoxemia (SpO₂ < 88%) within first 24 hours was associated with having a low number (≤4) of days alive and out of hospital within 14 days after admission: OR 2.4 (95%CI 1.2 to 4.8), p = 0.02, absolute risk 44% vs. 26% p = 0.01, Chi-square. Comparable results were observed after 30 days of follow-up: OR 2.6 (95% CI 1.0 to7.1), p = 0.05. A minimum of one measurement of hyperoxemia (SpO₂ > 92%), within first 24 hours of admission was not associated with low number of days alive and out of hospital within 14 days OR 1.0 (95% CI 0.5 to 2.1) nor at 30 days. Conclusion: For admitted patients with AECOPD, being hypoxemic ever within the first 24 hours after admission is associated with a substantially increased risk of a poor prognosis.