OBJECTIVES: The Huntington Quality of Life Instrument (H-QoL-I) is the first self-reported, disease-specific instrument developed to assess the health-related quality of life (HRQoL) of patients with Huntington’s disease (HD). It was originally developed and validated for France and Italy, and later also validated for Germany, Poland and the USA. This study aimed to validate the Spanish version of H-QoL-I cross-culturally. METHODS: The original questionnaire included three subscales assessing motor functioning, psychology and socializing (11 items). The instrument was translated forwards and backwards by native speakers. A survey was conducted with 59 patients. Face validity was tested through item completion and overall understanding. Internal validity was tested, assessing internal consistency, correlation matrix using item/dimension correlation and factorial structure. External validation was performed versus motor symptoms, behavioral symptoms, independence, and the EuroQoL 5D (EQ-5D).  Differential item functioning (DIF) analyses were performed versus data from the Italian and French versions, using Zumbo criteria. RESULTS: Item response rates ranged from 87% to 97%. A floor effect was found for three items. Results showed that the scale had a good reliability (Cronbach’s alpha coefficients > 0.75). Factor analyses demonstrated satisfactory construct validity. Item internal consistency (IIC) and item discriminant validity criteria were met for most items (i.e. IIC was > 0.40, and correlations between items and their respective rest-scores in one dimension were all greater than correlations with another dimension). The external validity was supported by correlation of the different dimensions with the related clinical symptoms and related generic QoL dimensions. The correlation between total H-QoL-I score and EQ-5D index score was 0.78.  No DIF was detected. CONCLUSIONS: These data support the cross-cultural validity of the H-QoL-I to assess the health status of patients with HD and integrate the patient perspective for Spain. A limitation of this study is the small sample size.