Intercellular adhesion molecule 1 (ICAM-1, CD54) binds to the integrin LFA-1 (CDlla/CD18), promoting cell adhesion in immune and inflammatory reactions. ICAM-is also subverted as a receptor by the major group of rhinoviruses. Electron micrographs show that ICAM-is a bent rod, 18.7 nm long, suggesting a model in which the five immunoglobulin-like domains are oriented head to tail at a small angle to the rod axis. ICAM-sequences important to binding LFA-1, rhinovirus, and four monoclonal antibodies were identified through the characterization of chimeric ICAM-molecules and mutants. The amino-terminal two immunoglobulinlike domains of ICAM-appear to interact conformationally. Domain 1 of ICAM-contains the primary site of contact for both LFA-1 and rhinovirus; the presence of domains 3-5 markedly affects the accessibility of the binding site for rhinovirus and less so for LFA-1. The binding sites appear to be distinct but overlapping; rhinovirus binding also differs from LFA-1 binding in its lack of divalent cation dependence. Our analysis suggests that rhinoviruses mimic LFA-1 in binding to the most membrane-distal, and thus most accessible, site of ICAM-1.