Purpose: In patients with COPD, one of the leading indications for domiciliary non-invasive ventilation (NIV), a major paradigm shift has been observed over the past decade in the method for adjusting NIV settings, with the use of sufficient ventilatory support to achieve a significant reduction in PaCO2. Whether this approach may be relevant to other populations, especially slowly progressive neuromuscular diseases (NMD), is unknown. Methods: This study was conducted as a post hoc analysis from a previously published randomized controlled trial (NCT03458507). Patients with NMD treated with domiciliary NIV were stratified according to the level of ventilatory support: high-level tidal volume (HLVT; mL/kg of predicted body weight [PBW]) or high-level pressure support (HLPS), defined as a value above median value of the whole population (> 6.8 mL/kgPBW or 9.0 cmH2O, respectively). Primary outcome was mean nocturnal transcutaneous CO2 pressure (PtcCO2). Secondary outcomes included adherence to NIV, leaks, and side effects. Results: Of a total of 26 patients, 13 were exposed to HLVT, with significantly lower nocturnal PtcCO2 (respectively 40.5 ± 4.2 vs. 46.3 ± 3.9 mmHg, p = 0.002). A linear correlation between VT (mL/kgPBW) and mean nocturnal PtcCO2 was evidenced (r = - 0.59, 95%CI [- 0.80; - 0.25], p = 0.002). No significant impact of HLVT was found on secondary outcomes. Conclusion: Despite the lack of power of this post hoc analysis, our results suggest that higher levels of ventilatory support are correlated with lower PtcCO2 in patients with NMD. Further studies are desirable to assess the extent to which the level of assistance influences PaCO2 evolution in patients with slowly progressive NMD, as well as in restrictive thoracic disorders.