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The spread of COVID-19 worldwide put the entire globe and the South American region in an urgent crisis. The global emergency has also generated new interests in greater national economic self-sufficiency and a turn towards sovereignty and bilateralism rather than regionalism. In South America, it has seriously hindered cooperation dynamics in a region already facing a profound social and economic crisis. COVID-19 arrived in a context of ideological polarisation among national governments and internal socio-political turmoil, which bode badly for its overlapping regional groupings. This context invites us to reflect on what a pandemic and post-pandemic moment might bring as regions become the terrain of competing ambitions between the US reclaiming pace in global politics and multilateralism, the European Union (EU) facing disintegration challenges, China motorising new forms of diplomacy and international cooperation, and Brazil retreating from regional leadership. This chapter introduces the framework for analysing the changes in cooperation dynamics in South American countries and the region’s main challenges in terms of regional and international cooperation. Contributing to the literature on the global political economy in Latin America, the chapter argues that ideological polarisation and lack of regional leadership have hindered cooperation outcomes addressing both extra-regional relations and intra-regional dynamics.