We provide evidence that the quasispecies nature (extreme genetic heterogeneity) of foot-and-mouth disease virus is relevant to the virus evading an immune response. A monoclonal antibody neutralizing the viral infectivity (clone SD6) recognizes an epitope located around a highly conserved sequence (amino acid sequence Arg-Gly-Asp-Leu-Ala at positions 141-145) in the capsid protein VP1 of foot-and-mouth disease virus of serotype C1. The amino acid substitutions Ala-138----Thr and Leu-147----Ile (or ----Val) reduced 100-fold the binding titer of monoclonal antibody SD6 to virions or to VP1. The effect of those substitutions was quantitatively reproduced with synthetic peptides representing the relevant sequences. This provides evidence that the two chemically conservative amino acids replacements--and not other substitutions present in the virus quasispecies--are responsible for the modified interaction with neutralizing monoclonal antibody SD6. The three substitutions were fixed in the viral capsid during one occurrence of foot-and-mouth disease and, furthermore, they are of a type found frequently among independent foot-and-mouth disease virus isolates. The results implicate the extreme heterogeneity of foot-and-mouth disease virus as an important element of viral pathogenesis.