Even early-treated phenylketonurics may suffer from phenylalanine-related deficits. Elevated phenylalanine concentrations can interfere with the development and function of the CNS. Outcome beyond childhood has not been extensively investigated. This long-term study was performed to determine whether adolescents and young adults with PKU show frontal lobe-dependent deficits when compared to diabetic patients. The comparative study covered 35 PKU patients, 13-21 years of age (mean 17.8 years), and 35 diabetic patients matched for sex, age and socioeconomic status. Patients were assessed for IQ (Culture Fair Intelligence Test), information processing (Trail Making Test), and selective and sustained attention (Stroop Task, Test d-2). Assessments were repeated within a 3-year follow-up. PKU patients showed no increase in blood phenylalanine concentrations at follow-up. They had significantly poorer test results than the diabetic patients at both assessment times. Within the tests, however, this was due to reduced performance speed but not to deficits in specific frontal lobe-dependent functions. Elevated phenylalanine concentrations seem to exert a global effect slowing performance speed. This effect is enduring in adolescence and early adulthood.