Carcinoembryonic antigen (CEA) expression is used clinically to monitor patients with colorectal and other cancers. A subset of patients have extraordinarily high CEA levels that cannot be attributed solely to tumor load. We have shown mutations in the region of CEA (PELPK motif) responsible for its hepatic clearance in three of eight patients with high CEA levels. We used denaturing high-performance liquid chromatography to provide evidence of polymorphism in these patients. These mutations were scored by DNA cycle sequencing and shown to be heterozygous. The patients with mutations in the PELPK motif showed remarkably reduced circulatory clearance rates in an animal model. A patient without mutation in the region showed normal clearance rates. Mutations in PELPK may affect structural stability and binding affinity to the Kupffer cell receptor in the liver. These studies have implications for the role of CEA as a facilitator of hepatic metastasis.