OBJECTIVES: The Huntington Quality of Life Instrument (H-QoL-I) is a first self-reported specific Health-Related Quality of Life (HR-QoL) instrument developed to assess the QoL of patients suffering from Huntington’s disease. It was originally developed and validated in French and in Italian. The instrument is being validated in 11 languages. This study aims to validate the German, Polish and US versions of H-QoL-I cross-culturally. METHODS: The original questionnaire was based on 11 items and 3 dimensions. The instrument was translated forwards and backwards by native speakers. It was then reviewed and adjusted by local clinicians and tested for face validity. A survey was conducted with 134 US, 60 Polish and 41 German patients. Face validity was tested through item completion and overall understanding. Internal validity was tested, assessing internal consistency, correlation matrix using item/dimension correlation, factorial structure and differential item functioning. External validation was performed versus motor symptoms, behavioral symptoms, and the well-established QoL scale EuroQoL 5D. RESULTS: The preliminary analysis supported the validity of the H-QoL-I. Face validity appeared satisfactory (Missing data < 7%); as for the original instrument, a ceiling effect was observed for patients with severe HD. The H-QoL-I showed an acceptable reliability (Cronbach’s alpha > 0.85 for each dimension). The factor analysis explained 77% of the total variance and split the items in 3 factors in the same way as the original version. There was no differential item functioning neither between countries nor gender. The Pearson’s correlation between the clinical motor score and the motor functioning dimension was 0.89, between EQ-5D score and H-QoL-I total score, 0.71 and between the clinical depression/anxiety score and the psychological dimension of H-QoL-I, 0.63. CONCLUSIONS: Test–retest and sensitivity to change remain to be performed, but current data support the validity of the H-QoL-I.