BACKGROUND: We estimate annual viral influenza-associated mild-to-moderate illness, hospitalizations, and deaths in 6 South American countries (Argentina, Brazil, Chile, Ecuador, Paraguay, and Uruguay) during the 2015-2019 influenza seasons as a first step in evaluating the full value of influenza vaccination in the subregion. METHODS: We applied a multiplier method using monthly hospital discharge and vital statistics death records, influenza surveillance data, and population projections to estimate mild-to-moderate influenza-associated illness, hospitalizations, and deaths. We estimated the uncertainty bounds based on the 2.5th and 97.5th percentiles of the Monte Carlo simulated distributions for the number of cases and obtained the ranges from the minimum value of the 2.5th and the maximum value of the 97.5th percentile. RESULTS: In selected countries with a total population of 307 million people, the yearly influenza-associated burden of disease ranged between 51 and 78 million mild-to-moderate influenza illnesses, between 323 379 and 490 049 hospitalizations, and between 22 662 and 46 971 deaths during the 2015-2019 influenza seasons. CONCLUSIONS: Each year, influenza is associated with millions of illnesses, hundreds of thousands of hospitalizations, and tens of thousands of deaths in 6 South American countries, affecting a significant portion of the population. Such findings can be used to estimate the number of illnesses averted through vaccination programs and the cost-benefit of influenza vaccines.