Objective: Social health preference sets are necessary for conducting health economic evaluations. Values from other countries are often used when local sets are not available, which may alter the results. We aimed to evaluate the degree of variability of currently available country-specific value sets of the EuroQol EQ-5D instrument from South American countries (SAC). Methods: We selected EQ-5D value sets from SAC and 2 reference countries. We obtained crosswalk value sets for the countries that use the EQ-5D-3L instrument. We compared the value sets with the Kruskal-Wallis test and then carried out pairwise comparisons with the Sign test. We also assessed correlations among the countries’ value sets using the Spearman test. We calculated the absolute difference across countries for each health state, considering a difference of greater than 0.05 relevant. Results: The range of value sets varied greatly. The Peruvian value set had the widest range (1 to −1.076) and the lowest values (median: 0.055; interquartile range: −0.171 to 0.275). The Ecuadorian set had the highest values (median: 0.587; interquartile range: 0.443-0.704). The Peruvian value set also had the greatest proportion of health states (43.6%) with a negative value, and the Uruguayan set had the smallest proportion (0.9%). Differences among countries were significant in all cases, with the greatest difference between Ecuador and Peru (median difference: 0.495; 95% confidence interval: 0.515–0.528). Conclusion: Social health preference sets varied greatly among SAC. Using non-local values could distort resource allocation decisions; hence, we recommend that countries obtain and use local value sets.