Aim of the study was the evaluation of health-related quality of life (HRQoL) and the detection of deviant behavior in early-treated children and adolescents with PKU in comparison with healthy peers. Special focus was laid on the impact of compliance with treatment as defined by the national recommendations on HRQoL. Our investigation in 50 children and adolescents and their parents for the first time demonstrates that despite an overall normal HRQoL in our PKU patient collective, parents are concerned about performance in school especially when phenylalanine concentrations in their children are mainly above the therapeutic range. Adherence to target phenylalanine concentrations ameliorated markedly in patients above 10 years in comparison to younger patients due to relaxed treatment recommendations. Interestingly, this alleged improvement in metabolic control has an impact on the parent assessed but not on the patient assessed appraisal of HRQoL. However, a positive correlation between poor metabolic control and conduct problems was identified by patients' self-assessment. In conclusion, lacking adherence to the strict treatment recommendations in infancy results in significant concern about school success and success in life in parents of PKU patients. With relaxation of dietary phenylalanine restriction at 10 years of age, these concerns diminish.