Analysis of mouse cDNA clones has led to the identification of a class I (H-2)-related gene that encodes a truncated transplantation-like antigen. Unlike the products of the class I genes (H-2K, H-2D, and H2-L), which are synthesized and displayed on the surface of all cells, the class I-related gene product is expressed only in liver cells and is secreted. The region of the secreted molecule corresponding to the extracellular domain of the membrane-bound class I antigens shows unusual amino acid substitutions at positions otherwise invariably conserved. There is also loss of a glycosylation site that is used in all class I antigens. Within the region corresponding to the transmembrane domain are multiple nonconservative substitutions of hydrophobic residues, alterations that render the encoded protein incapable of inserting into the plasma membrane. Toward the end of the same domain, the polypeptide chain terminates abruptly and thus lacks the intracellular domain present on all class I antigens. A candidate for this secreted molecule, detected using various heteroantisera against class I antigens, has been identified. A potential role for this serum protein in mediating active tolerance is discussed.