Picornavirus RNAs initiate translation using an internal ribosome entry site (IRES)-dependent mechanism. The IRES element of foot-and-mouth disease virus (FMDV) is organized in domains, being different from each other in RNA structure and RNA-protein interaction. Wild-type transcripts provided in trans rescue defective FMDV IRES mutants. Complementation, however, was partial since translation efficiency of the mutant RNAs was up to 10% of the wild type IRES. We report here that mutations diminishing the RNA-RNA interaction capacity induced a decrease in IRES rescue. On the other hand, IRES transcripts bearing mutations that reorganize the RNA structure of the apical region of central domain, although weakly, complement defective IRES that are unable to interact with the initiation factor eIF4G in a separate domain. Together, these results suggest that IRES rescue may involve RNA-mediated contacts between defective elements, each carrying a defect in a separate domain but having the complementing one with the appropriate structural orientation and/or ribonucleoprotein composition. Our observations further support the essential role of the central domain of the FMDV IRES during protein synthesis and demonstrate that there is a division of functions between the IRES domains.