OBJECTIVES Phenylketonuria (PKU) is a rare genetic disorder impacting phenylalanine (Phe) metabolism. Treatment involves a lifelong Phe restricted diet that is strict and socially demanding. Even when treated early and well, mild cognitive abnormalities have been seen. PKU can affect quality of life in individuals and their families. The phenylketonuria–quality of life (PKU-QOL) questionnaires are the first PKU-specific QOL questionnaires ever developed. The study aimed to perform the psychometric validation of these questionnaires. METHODS An observational study was conducted in France, Germany, Italy, The Netherlands, Spain, Turkey and the UK to finalize and validate PKU-QoL questionnaires in individuals with treated PKU aged 9–11, 12–17 and ≥18 years, and in parents of individuals <18 years. Questionnaires were assessed for reliability (internal consistency, test–retest), concurrent validity (using three generic questionnaires adapted to the respondent: PedsQOL, SF-36 for adults and CHQ-PF28) and clinical validity (using PKU severity and overall assessment of patient health status). RESULTS In total, 559 participants (306 individuals, ages 9–45 years; 253 parents, ages 24–66 years) were included in the analysis. Return rate and quality of completion of the questionnaires were good, indicating good acceptability. Scores were defined to assess all relevant aspects of experiences: PKU symptoms, impact of PKU, dietary protein restriction and supplementation. Reliability and validity were satisfactory overall for the adolescent, adult and parent PKU-QoL questionnaires, and slightly weaker but acceptable for the child version. CONCLUSIONS The four PKU-QOL questionnaires are valid and reliable instruments for assessing the specific quality of life aspects that are affected in individuals with PKU of different age groups (children, adolescents and adults) and their parents, and are available in seven languages. They are very promising tools for focused evaluation of PKU impact on individuals and parents in different countries, and for monitoring the efficacy of therapeutic strategies.