A cDNA clone homologous to the mouse lymph node homing receptor core protein (mLHRc) was isolated from a cDNA library derived from stimulated human peripheral blood lymphocytes. Human RNA blot analysis shows a tissue and cell-line distribution of transcript expression generally parallel to that seen in the mouse, with expression confined to lymphoid tissues and some cell lines. Genomic DNA analysis suggests a low-copy gene under high-stringency conditions. The complete nucleotide sequence predicts a mature protein of 334 amino acids, identical in length to mLHRc. The protein shows striking conservation globally between human and mouse sequences. In particular, all three genre of protein interaction domains identified in the mouse--an animal lectin domain, an epidermal growth factor (EGF)-like domain, and two homologous repeat units preserving the motif of complement regulatory proteins (CRP)--are present in the human protein (hLHRc), and maintain the same tandem arrangement. The lectin and EGF-like regions are the most homologous, while the CRP domains are less conserved between species. The two CRP units in hLHRc are distinct from those in mLHRc in that they are homologous to one another rather than identical, suggesting strong pressure for maintenance of two repeats in this molecule. hLHRc is distinct from other kinds of lymphocyte adhesion molecules represented by VLA-4 (integrin) or CD44/gp90Hermes and, together with mLHRc and two other recently described molecules having a similar domain motif, defines a novel class of adhesion molecules exhibiting distinct evolutionary features. We propose that hLHRc likely represents the protein core of the human homologue of mLHRc functionally as well as structurally.