Background: Disturbances of intestinal integrity, manifested by increased gastro-intestinal (GI) permeability, have been found in chronic obstructive pulmonary disease (COPD) patients during physical activity, often associated with intermittent hypoxic periods. Evidence about extrapulmonary organ disturbances, especially of the GI tract, during hospitalised acute exacerbation of COPD (AE-COPD) with hypoxaemic respiratory failure (RF) is lacking. Objective: The aim was to assess changes in GI permeability in patients with AE-COPD and during recovery 4 weeks later. Methods: All patients admitted to our hospital with AE-COPD accompanied by hypoxaemia at admission (PaO2 <8.7 kPa or O2 saturation <93%) were screened between October 2013 and February 2014. Patients with a history of GI or renal disease, chronic heart failure, or use of non-steroidal anti-inflammatory drugs in the 48 h before the test were excluded. GI permeability was assessed by evaluating urinary excretion ratios of the orally ingested sugars lactulose/L-rhamnose (L/R ratio), sucrose/L-rhamnose (Su/R ratio) and sucralose/erythritol (S/E ratio). Results: Seventeen patients with severe to very severe COPD completed the study. L/R ratio (×103) at admission of AE-COPD was significantly higher than in the recovery condition (40.9 [29.4–49.6] vs. 27.3 [19.5–47.7], p = 0.039), indicating increased small intestinal permeability. There were no significant differences in the individual sugar levels in urine nor in the 0- to 5-h urinary S/E and Su/R ratios between the 2 visits. Conclusion: This is the first study showing increased GI permeability during hospitalised AE-COPD accompanied by hypoxaemic RF. Therefore, GI integrity in COPD patients is an attractive target for future research and for the development of interventions to alleviate the consequences of AE-COPD.