The plasma pipecolic acid concentration in two newborn infants with Zellweger syndrome at ages 4 and 10 days were 7.8 and 7.7 microM. Reported concentrations from this laboratory for normal newborn infants averaged 12 microM +/- 5.6 (SD). Both patients had the facies and severe hypotonia characteristic of the disease. Autopsy examination at age 6 days in one of these patients revealed the developmental microscopic abnormalities in brain, liver, and kidney that are associated with Zellweger syndrome. In three additional patients ages 3 1/2 weeks, 2 months, and 2 months, the pipecolic acid concentrations were 15, 17, and 25 microM. The concentrations increased to distinctly pathological levels on subsequent assays at a later age. It is concluded that the hyperpipecolatemia in Zellweger syndrome occurs postpartum and that the plasma concentrations may not be diagnostic early in life. The major manifestations of the disease, already evident at birth, cannot be attributed to pipecolatemia. Currently available data do not exclude the possibility of pipecolic acid accumulation in the brain where it has been reported to be a major metabolite of lysine. Hyperpipecolatemia of considerable degree is also consistently found in familial hyperlysinemia where it appears to be benign.