Histidine-rich glycoprotein (HRG) is a plasma protein of vertebrates that has been implicated in the regulation of several important biological functions, including the immune response and blood clotting. In the present study, we have isolated and determined the sequence of the cDNAs for both mouse and rat HRG. The deduced amino acid sequences of mouse and rat HRG are 525 and 510 amino acids, respectively, and they show the same three-domain structure that has been predicted for human HRG, with which they share high amino acid identity. Northern blot analysis indicates that the mouse HRG mRNA is 1.7 kb and is localized specifically to the liver. It has been suggested, somewhat controversially, that some immune cells, such as monocytes and megakaryocytes, also synthesize HRG. Reverse transcriptase-polymerase chain reaction analysis has failed to show any HRG mRNA in immune tissues of the mouse, including the spleen, thymus, lymph node, bone marrow and peripheral blood leucocytes. These data suggest that HRG expression by immune cells is due to the acquisition of plasma HRG derived from the liver. Finally, genomic Southern blot analysis of the mouse HRG gene suggests that it is a single copy gene.