At present, Foot-and-Mouth Disease (FMD) has been successfully controlled in most territories of South America, where only Ecuador and Venezuela remain as endemic countries. In this context, the precise characterization of circulating viruses is of utmost importance. This work describes the first molecular epidemiology study performed with the complete VP(1)-coding region of 114 field isolates of FMD virus (FMDV) type O, collected in the Andean countries mainly during 2002-2008. Sequences were aligned and compared to isolates responsible for emergencies in the Southern Cone of the continent between the years 2000 and 2006, and to other representative type O viruses worldwide. The results showed that FMD type O viruses isolated in South America and analyzed up to date are placed in 11 different lineages within the Euro SA topotype. Five of these lineages included viruses circulating in Ecuador and Venezuela during 2002-2008. The last emergencies reported in already-free areas in the Andean region, showed close relationships with viruses circulating in these endemic countries. Andean lineages showed a clear separation from the unique lineage containing viruses responsible for the emergencies in the Southern Cone, reflecting the different livestock circuits and providing evidence that support the ecosystem dynamics in the region. A wide geographical dissemination of the same strain in short time intervals has been observed, pointing to animal movements as the most significant risk parameter. This fact, together with an important generation of viral variants in areas under weak control strategies, reinforce the need of stronger official controls, as well as for establishing multinational cooperative measures in the border areas.