Prenatal diagnosis of classic phenylketonuria (PKU) was performed in two at-risk families by means of a cloned human phenylalanine hydroxylase gene probe which was used to analyse DNA isolated from cultured amniotic fluid cells. The diagnoses of a PKU fetus in one family and a heterozygous fetus in another family were confirmed after birth. The prenatal diagnosis procedure by DNA analysis can be confidently applied to 90% of caucasian families with previously affected children.