The primary structure of VP3, VP2 and VP4 capsid protein genes has been determined for six epizootiologically-related foot-and-mouth disease virus (FMDV) isolates of serotype C1, two of which presented immunogenic differences as determined by a cross-protection assay. The results obtained have been compared with those previously reported for the corresponding VP1 genes Martinez et al. (1988) Gene 62, 75-84. High rates of fixation of mutations have been estimated for the four capsid protein genes that ranged from 3.9 X 10(-4) to 4.5 X 10(-3) substitutions per nucleotide per year, with the highest values corresponding to VP1. Despite this genetic heterogeneity most of the amino acid exchanges are within the VP1 protein. Of the fourteen amino acid substitutions one was located in VP2 and two in VP3. Five out of the eleven amino acid exchanges that affected VP1 were located within residues 138-149, part of a main immunogenic site in FMDV. These results show that in the course of a foot-and-mouth disease outbreak, immunologically relevant amino acid substitutions occur mainly in viral capsid protein VP1.