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Objectives The aim of our study was to evaluate the usefulness of systemic immune-inflammation index (SII) at admission in predicting in-hospital mortality in patients with infective endocarditis. Methods 133 definite IE patients (≥18 years) according to modified Duke criteria, treated in our tertiary care hospital between December 2009 and May 2019, were retrospectively analysed. Symptoms, comorbidities, predisposing valvular diseases, prosthetic valve, device, history of injectable drug use, blood culture results, echocardiography findings, and complications were collected. We calculated the SII as follows: SII = platelet count × neutrophil count/lymphocyte count at admission. Results The median age of the patients was 56 (40–66) years. Prosthetic valve disease was the most frequent predisposing valve lesion. Staphylococcus species were the most common microorganisms. The most frequent complication was in-hospital mortality (22%) followed by renal failure. Older population, syncope, increased inflammatory markers, high systolic pulmonary artery pressure (PAPs), heart failure, renal failure, and septic shock were associated with high mortality. However age, syncope, hypocalcemia, not going to surgery, and SII were independent predictors of in-hospital mortality. According to receiver operating characteristic curve analysis, the optimal SII cut-off value for predicting mortality was 2314 (area under the curve 0.641; P = 0.019). Conclusion We demonstrated that high SII levels are independently associated with in-hospital mortality. The SII may be a promising prognostic predictor for patients with infective endocarditis.