Rhinoviruses belong to the picornavirus family and cause about 50% of common colds. Most rhinoviruses and some coxsackie viruses share a common receptor on human cells. The glycoprotein intercellular adhesion molecule-1 (ICAM-1) has recently been identified as the cellular receptor for the subgroup of rhinoviruses known as the major groups. ICAM-1 is a member of the immunoglobulin supergene family and is a ligand for lymphocyte function-associated antigen-1 (LFA-1); these ICAM-1/LFA-1 interactions are critical to many cell adhesion processes involved in the immunological response. Because anti-ICAM-1 antibodies can block binding of major-group rhinoviruses to cells, we considered that antagonism of virus-receptor interaction might be a way of preventing rhinovirus infection. We have constructed and purified a soluble form of the ICAM-1 molecule, which is normally membrane-bound, and demonstrated that it is a potent and specific inhibitor of rhinovirus infection.