We assessed the relationship between anxiety and long-term metabolic control in adolescents with phenylketonuria (PKU). We used a standardized psychological test to measure anxiety level and analyzed lifelong blood phenylalanine stability in a selected group of 25 PKU teenagers with treatment adherence problems. We demonstrated significant correlations of anxiety with variability of blood phenylalanine concentrations and with severity of hyperphenylalaninemia. Avoiding blood phenylalanine fluctuations in childhood can probably reduce anxiety in PKU adolescents.