Abstract Background Tidal expiratory flow limitation (EFL_T) promotes intrinsic PEEP (PEEPi) in patients with chronic obstructive pulmonary disease (COPD). Applying non-invasive ventilation (NIV) with an expiratory positive airway pressure (EPAP) matching PEEPi improves gas exchange, reduces work of breathing and ineffective efforts. We aimed to evaluate the effects of a novel NIV mode that continuously adjusts EPAP to the minimum level that abolishes EFL_T. Methods This prospective, cross-over, open-label study randomized patients to one night of fixed-EPAP and one night of EFL_T-abolishing-EPAP. The primary outcome was transcutaneous carbon dioxide pressure (PtcCO₂). Secondary outcomes were: peripheral oxygen saturation (SpO₂), frequency of ineffective efforts, breathing patterns and oscillatory mechanics. Results We screened 36 patients and included 12 in the analysis (age 72 ± 8 years, FEV1 38 ± 14%Pred). The median EPAP did not differ between the EFL_T-abolishing-EPAP and the fixed-EPAP night (median (IQR) = 7.0 (6.0, 8.8) cmH₂O during night vs 7.5 (6.5, 10.5) cmH₂O, p = 0.365). We found no differences in mean PtcCO₂ (44.9 (41.6, 57.2) mmHg vs 54.5 (51.1, 59.0), p = 0.365), the percentage of night time with PtcCO₂ > 45 mm Hg was lower (62(8,100)% vs 98(94,100)%, p = 0.031) and ineffective efforts were fewer (126(93,205) vs 261(205,351) events/hour, p = 0.003) during the EFL_T-abolishing-EPAP than during the fixed-EPAP night. We found no differences in oxygen saturation and lung mechanics between nights. Conclusion An adaptive ventilation mode targeted to abolish EFL_T has the potential to reduce hypercapnia and ineffective efforts in stable COPD patients receiving nocturnal NIV. Trial registration: ClicalTrials.gov, NCT04497090. Registered 29 July 2020—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04497090.