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The coronavirus disease 2019 (COVID-2019) pandemic struck Latin America in late February and is now beginning to spread across the rural indigenous communities in the region, home to 42 million people. Eighty percent of this highly marginalized population is concentrated in Bolivia, Guatemala, Mexico and Peru. Health care services for these ethnic groups face distinct challenges in view of their high levels of marginalization and cultural differences from the majority. Drawing on 30 years of work on the responses of health systems in the indigenous communities of Latin America, our group of researchers believes that countries in the region must be prepared to combat the epidemic in indigenous settings marked by deprivation and social disparity. We discuss four main challenges that need to be addressed by governments to guarantee the health and lives of those at the bottom of the social structure: the indigenous peoples in the region. More than an analysis, our work provides a practical guide for designing and implementing a response to COVID-19 in indigenous communities.