Background: Evaluation of health-related quality of life (HRQL) in chronic respiratory failure (CRF) is an important issue for evaluating the impact of treatment. Objectives: To elaborate a French version of the Maugeri Foundation Respiratory Failure Questionnaire (MRF-28) disease-specific HRQL questionnaire and determine its validity and reliability in patients with CRF treated by home mechanical ventilation (HMV). Methods: Forward- and back-translation of the MRF-28 questionnaire; the final version was submitted to 81 patients treated with HMV for CRF, simultaneously with the St. George’s Respiratory Questionnaire (SGRQ), the Short Form 36 (SF-36), and the Hospital Anxiety and Depression scale (HAD). Validity was determined by correlation with previously validated HRQL scores and recorded physiological parameters. Reliability was evaluated by assessing internal consistency and test-retest stability of the MRF-28 scores. Results: The French version of the MRF-28 and its subscores (‘daily activity’, ‘cognitive function’, and ‘invalidity’) were highly significantly correlated with subscores of the SGRQ, the SF-36 and the HAD. Both the MRF-28 and the SGRQ were correlated only with age and the 6-min walk test. The MRF-28 showed high test-retest reliability after 2 weeks (r² = 0.80, p < 0.0001) and high internal consistency (Crohnbachs’ α coefficient: 0.91). Conclusion: The French version of the MRF-28 is a valid and reliable disease-specific questionnaire for assessing HRQL in patients with CRF.