From 1 January 2007 an expanded neonatal screening programme was initiated in the Netherlands, including homocystinuria with methionine as the primary marker. During the first 2 months hypermethioninaemia was detected in 14 newborns who, after proper evaluation, were demonstrated not to have classical homocystinuria. Remarkably, all these children were admitted to a single neonatal intensive care unit (Academic Medical Center, Amsterdam (AMC-NICU)). We evaluated the possible causes for this finding. The cohort of newborns with hypermethioninaemia (group 1) was compared with the cohort of newborns with normal screening results admitted to the AMC-NICU in the same time period (group 2). In addition, parenteral nutrition protocols from all NICUs in the Netherlands were compared. Mean birth weight and gestational age were significantly lower in group 1 than in group 2. All patients in group 1 received parenteral feeding (TPN) at the time of screening and received a higher mean amino acid intake per kilogram body weight than patients receiving TPN in group 2. Also, the AMC-NICU uses a different amino acid mixture for TPN than the other Dutch NICUs, containing more than twice the amount of methionine per gram of amino acids compared with other mixtures. The high incidence of hypermethioninaemia in the AMC-NICU is explained by a combination of low birth weight, low gestational age, and high protein intake supplied by a specific parenteral amino acid mixture containing large amounts of methionine. To prevent hypermethioninaemia, the use of high-methionine containing solutions for TPN should be reconsidered.