Objective: To validate prospectively in multiple centers, the accuracy and clinical utility of the European System for Cardiac Operative Risk Evaluation (EuroSCORE II) to predict the operative mortality of cardiac surgery in Argentina. Methods: Between January 2012 and February 2018, 2000 consecutive adult patients who underwent cardiac surgery in different centers in Argentina were prospectively included. The endpoint was in-hospital all-cause mortality. Discrimination, calibration, precision, and clinical utility of the EuroSCORE II were evaluated in the global cohort and in the different types of surgeries, based on receiver operating characteristics (ROC) curves, Hosmer-Lemeshow goodness-of-fit test, observed/expected mortality ratio, Shannon index, and decision curves analysis. Results: ROC area of the EuroSCORE II was between 0.73 and 0.80 for all types of surgery, being the lowest value for coronary surgery. The observed and expected mortality was 4.3% and 3.0%, respectively (p = 0.034). The decision curve analysis showed a positive net benefit for all thresholds below 0.24, considering all type of surgeries. Conclusions: The EuroSCORE II showed an adequate performance in terms of discrimination and calibration for all types of surgery, although somewhat inferior for coronary surgery. Although, in general terms, this model underestimated the risk in intermediate-risk groups, its overall performance was acceptable. The EuroSCORE II could be considered an optional updated generic model of operative risk stratification to predict in-hospital mortality after cardiac surgery in our context.