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To develop and validate a calculator to predict the risk of in-hospital mortality in patients with active infective endocarditis (IE) undergoing cardiac surgery.Thousand two hundred and ninety-nine consecutive patients with IE were prospectively recruited (1996–2014) and retrospectively analysed. Left-sided patients who underwent cardiac surgery (n=671) form our study population and were randomised into development (n=424) and validation (n=247) samples. Variables statistically significant to predict in-mortality were integrated in a multivariable prediction model, the Risk-Endocarditis Score (RISK-E). The predictive performance of the score and four existing surgical scores (European System for Cardiac Operative Risk Evaluation (EuroSCORE) I and II), Prosthesis, Age ≥70, Large Intracardiac Destruction, Staphylococcus, Urgent Surgery, Sex (Female) (PALSUSE), EuroSCORE ≥10) and Society of Thoracic Surgeons’s Infective endocarditis score (STS-IE)) were assessed and compared in our cohort. Finally, an external validation of the RISK-E in a separate population was done.Variables included in the final model were age, prosthetic infection, periannular complications, Staphylococcus aureus or fungi infection, acute renal failure, septic shock, cardiogenic shock and thrombocytopaenia. Area under the receiver operating characteristic curve in the validation sample was 0.82 (95% CI 0.75 to 0.88). The accuracy of the other surgical scores when compared with the RISK-E was inferior (p=0.010). Our score also obtained a good predictive performance, area under the curve 0.76 (95% CI 0.64 to 0.88), in the external validation.IE-specific factors (microorganisms, periannular complications and sepsis) beside classical variables in heart surgery (age, haemodynamic condition and renal failure) independently predicted perioperative mortality in IE. The RISK-E had better ability to predict surgical mortality in patients with IE when compared with other surgical scores.