BACKGROUND: We quantify the mortality burden and economic loss attributable to nonoptimal temperatures for cold and heat in the Central and South American countries in the Multi-City Multi-Country (MCC) Collaborative Research Network. METHODS: We collected data for 66 locations from 13 countries in Central and South America to estimate location-specific temperature-mortality associations using time-series regression with distributed lag nonlinear models. We calculated the attributable deaths for cold and heat as the 2.5th and 97.5th temperature percentiles, above and below the minimum mortality temperature, and used the value of a life year to estimate the economic loss of delayed deaths. RESULTS: The mortality impact of cold varied widely by country, from 9.64% in Uruguay to 0.22% in Costa Rica. The heat-attributable fraction for mortality ranged from 1.41% in Paraguay to 0.01% in Ecuador. Locations in arid and temperate climatic zones showed higher cold-related mortality (5.10% and 5.29%, respectively) than those in tropical climates (1.71%). Arid and temperate climatic zones saw lower heat-attributable fractions (0.69% and 0.58%) than arid climatic zones (0.92%). Exposure to cold led to an annual economic loss of $0.6 million in Costa Rica to $472.2 million in Argentina. In comparison, heat resulted in economic losses of $0.05 million in Ecuador to $90.6 million in Brazil. CONCLUSION: Most of the mortality burden for Central and South American countries is caused by cold compared to heat, generating annual economic losses of $2.1 billion and $290.7 million, respectively. Public health policies and adaptation measures in the region should account for the health effects associated with nonoptimal temperatures.