Foot-and-mouth disease virus appears to initiate infection by binding to cells at an Arg-Gly-Asp (RGD) sequence found in the flexible beta G-beta H loop of the viral capsid protein VP1. The role of the RGD sequence in attachment of virus to cells was tested by using synthetic full-length viral RNAs mutated within or near the RGD sequence. Baby hamster kidney (BHK) cells transfected with three different RNAs carrying mutations bordering the RGD sequence produced infectious viruses with wild-type plaque morphology; however, one of these mutant viruses bound to cells less efficiently than wild type. BHK cells transfected with RNAs containing changes within the RGD sequence produced noninfectious particles indistinguishable from wild-type virus in terms of sedimentation coefficient, binding to monoclonal antibodies, and protein composition. These virus-like particles are defined as ads- viruses, since they were unable to adsorb to and infect BHK cells. These mutants were defective only in cell binding, since antibody-complexed ads- viruses were able to infect Chinese hamster ovary cells expressing an immunoglobulin Fc receptor. These results confirm the essential role of the RGD sequence in binding of foot-and-mouth disease virus to susceptible cells and demonstrate that the natural cellular receptor for the virus serves only to bind virus to the cell.