Introduction Domiciliary High-flow, humidified, nasal cannula (HFNC) is a possible add-on in patients with chronic respiratory diseases. This post-hoc study investigates benefit of HFNC in subgroups of advanced COPD patients with chronic hypoxic failure on reduction of exacerbations and hospitalizations. Methods One hundred patients were randomized to HFNC in a previous trial. Subgroups with 0-1 (N = 32) respectively two or more (2+) (N = 68) exacerbations 12 months pre-study were investigated. Changes in number of exacerbations and hospitalizations pre- and in study were analyzed, corrected for HFNC days with HFNC. Results Patients were comparable at baseline. Exacerbations increased in subgroup 0-1 (p = 0.01) and decreased in subgroup 2+ (p = 0.03). Correcting for HFNC days no correlation was seen in subgroup 0-1 (p = 0.08), but in subgroup 2+ (p<0.001). Number of hospitalizations increased in subgroup 0-1 (p = 0.01) with no change in days of hospitalization (p = 0.08). Number and days of hospitalization decreased in subgroup 2+ (p = 0.002 resp. 0.025). Correcting for HFNC days no correlation was found in number or days of hospitalization in subgroup 0-1 (p = 0.48 and p = 0.65). Positive correlation was found in subgroup 2+ (both p<0.001). Conclusion In patients with advanced COPD, chronic hypoxic failure and two or more exacerbations per year, HFNC significantly reduced exacerbations and hospitalizations.