In patients with chronic respiratory failure, home non-invasive ventilation (NIV) is delivered through nasal or oronasal masks. Masks are a cornerstone for NIV success but can be associated with side effects. However, the type, the frequency and the consequences of these side effects are unknown. Here, we aimed to study the prevalence, nature, and impact of mask-related adverse events in a cohort of stable patients. We then investigated differences between oronasal and nasal masks both in our cohort and in a bench study. Prospective observational cohort including patients established on long-term non-invasive ventilation admitted for their elective review. Data regarding mask-related side effects were assessed using a structured questionnaire. Our bench study was performed using a 3-D printed head connected to an artificial lung. Eight hundred patients were included of whom, 84% had a oronasal mask. Moderate to very severe mask-related side effects occurred in 47% of patients and severe to very severe side effects occurred in 18%. Side effects were associated to a poorer daytime PaCO2 (p=0.005), poorer subjective sleep quality (p=0.003), poorer quality of life (p<0.001). Mask-related side effects were more frequently reported with the use of oronasal masks as compared to nasal masks (p=0.023). Our bench study showed that nasal masks were more stable than oronasal masks (p<0.001). Mask-related side effects are frequent and associated with poorer outcome. Our data suggest that nasal masks may have a better tolerance profile and should be used as a first-line interface.