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Introduction: Despite diagnostic and therapeutic advances, infective endocarditis (IE) remains a challenging and potentially lethal disease. The prognosis of IE remains poor; in the last 30 years, its incidence and mortality have only been marginally reduced. Early identification of high-risk patients can change the course of the disease and improve outcomes., Objectives and Methods: To describe and investigate predictors of mortality during hospital stay and in the six months after discharge in a cohort of left-sided IE patients in two tertiary centers. All patients diagnosed with IE (ICD9 code 133) were registered in a uniform database., Results: One hundred and forty-seven consecutive case patients with left-sided IE were included in this study. Thirty-five patients (23.8%) died during hospital stay. The variables significantly associated with increased mortality in univariate analysis were Charlson index ≥ 5, use of immunosuppressants, sepsis (severe sepsis and/or septic shock), cardiogenic shock and inappropriate use of antibiotic therapy. Conversely, surgical therapy and hospital length of stay ≥ 30 days were significantly associated with lower mortality. In multivariate analysis the most important predictors of in-hospital mortality were sepsis (severe and/or shock), use of immunosuppressants and inappropriate use of antibiotic therapy. There was a significant relation between the use of immunosuppressants and the occurrence of sepsis. The presence of significant valve disease after IE significantly increased the risk of heart failure., Conclusions: Our results may help to identify IE patients at increased risk for in-hospital mortality and medium-term disability. These findings can help to identify candidates for earlier and more aggressive management., (Copyright © 2012 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.)