The site on nectin1 receptor required for herpes simplex virus (HSV) entry into the cell was previously mapped to the 64-94 region, encompassing the predicted CC'C" region of the immunoglobulin V domain. Within it lies a minimal HSV entry site (residues 77-94). Here we transferred the 65-76 region (C strand and CC' loop) and portions, or single amino acids, thereof to nectin2, a homolog nonfunctional for wt HSV-1 entry. Replacement of the seven- or of three-amino-acid-long stretches from nectin1 to nectin2 (amino acids 69-75, 69-71, or 72-75) transferred wt HSV-1 and BHV-1 entry activity and enhanced HSV-2, PrV, and HSV-HSV(U21) entry to levels observed with nectin1. Thus, the CC' ridge is sufficient to mediate wt HSV entry at a reduced level and responsible for the wide virus range of the receptor. Altogether the HSV entry site appears to be composed of contiguous synergistic regions, 64-76 and 77-94, each independently capable of mediating virus entry at reduced efficiency.