It is a challenge to control oxygen saturation (SpO ₂ ) in patients with exacerbations of COPD during admission. We tested a newly developed closed-loop system, O2matic®, and its ability to keep SpO ₂ within a specified interval compared with manual control by nursing staff. Patients and methods: We conducted a crossover trial with patients admitted with an exacerbation of COPD and hypoxemia (SpO ₂ ≤88% on room air). Patients were monitored with continuous measurement of SpO ₂ . In random order, they had 4 hours with manually controlled oxygen and 4 hours with oxygen delivery controlled by O2matic. Primary outcome was time within a prespecified SpO ₂ target interval. Secondary outcomes were time with SpO ₂ <85%, time with SpO ₂ below target but not <85%, and time with SpO ₂ above target. Results: Twenty patients were randomized and 19 completed the study. Mean age was 72.4 years and mean FEV1 was 0.72 L (33% of predicted). Patients with O2matic-controlled treatment were within the SpOF target interval in 85.1% of the time vs 46.6% with manually controlled treatment (P<0.001). Time with SpO ₂ <85% was 1.3% with O2matic and 17.9% with manual control (P=0.01). Time with SpO ₂ below target but not <85% was 9.0% with O2matic and 25.0% with manual control (P=0.002). Time with SpO ₂ above target was not significantly different between treatments (4.6% vs 10.5%, P=0.2). Patients expressed high confidence and a sense of safety with automatic oxygen delivery. Conclusion: O2matic was able to effectively control SpO ₂ for patients admitted with an exacerbation of COPD. O2matic was significantly better than manual control to maintain SpO ₂ within target interval and to reduce time with unintended hypoxemia.