Introduction Mouthpiece ventilation represents a valuable treatment for patients needing daytime non-invasive ventilation. This modality is however underused, in part because of limitations in the available equipment. Objective To develop a new flexible and moldable mouthpiece, aiming to address some of the issues of the currently available interfaces. Methods We compared 2 commercially available and the newly developed mouthpieces in a bench test using 4 life-support home ventilators and 3 settings per ventilator. Results The 3 interfaces showed marked differences in their resistive characteristics. In the volume-controlled setting (VC-CMV) with 500 ml tidal volume (VT), the delivered VT, ranged between 459 ±7 ml (-8%) and 501 ±4 ml (+0.2%), according to the used ventilator. In the VC-CMV setting with VT 1000 ml, one of the ventilators did not assure the set VT with the new mouthpiece, because of the high-pressure limitation. In the pressure-controlled setting (PC-CMV at 20 cmH2O), the effective pressure differed between the tested interfaces according to their resistance, resulting in a decrease in the delivered VT. Conclusions We found measurable differences in the ventilation's performances comparing the interfaces for mouthpiece ventilation, which seem to have a minor clinical relevance in the most settings, but should be systematically checked. We validated in-vitro the newly developed mouthpiece with respect to the ventilation performances; a clinical study is needed to investigate the potential advantages we expect from the new mouthpiece. This article is protected by copyright. All rights reserved.