The lymph node homing receptor core polypeptide (mLHRc) is composed of a tandem collection of domains: a lectin domain, an epidermal growth factor (EGF) domain, and two repeats common in complement regulatory proteins. Here we demonstrate localization of mLHRc to chromosome 1, the portion syntenic with chromosome 1 in man. This locus is inseparable in mouse strains from the murine lymphocyte cell surface marker Ly-22. The data indicate that Ly-22 is an allelic determinant on the LHR resulting from a single amino acid interchange within the EGF domain. Cross-blocking experiments demonstrate that anti-Ly-22 and MEL-14 recognize independent epitopes and that Ly-22 is distinct from the carbohydrate binding region. Application of anti-Ly-22 in the in vitro binding assay shows inhibition of binding of lymphocytes to high endothelial venules (HEVs). The localization of the Ly-22 epitope in this novel chimeric protein suggests direct participation of the EGF domain in the adhesion of lymphocytes to HEV.