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Background: The early identification of patients at risk of complications of infective endocarditis (IE) using parameters obtained as part of routine practice is essential for guiding clinical decision-making. This study aimed to identify a parameter at hospital admission that predicts the outcome, adding value to other well-known factors of a poor prognosis in IE. Methods: Two hundred and three patients with IE were included in this study. Clinical evaluation, echocardiography, blood cultures, and routine laboratory tests were performed at hospital admission. The endpoint was in-hospital mortality. Results: The mean age of the patients was 48.2 ± 16.6 years; 62% were male and 38% had rheumatic heart disease. During treatment, cardiac surgery was performed in 111 patients (55%), and the overall in-hospital mortality rate was 32%. In the multivariable analysis, the independent predictors of death were age (odds ratio (OR) 1.07, 95% confidence interval (CI) 1.02–1.13), C-reactive protein (CRP) at hospital admission (OR 1.12, 95% CI 1.04–1.21), length of the vegetation at diagnosis (OR 1.15, 95% CI 1.03–1.28), development of heart failure (OR 6.43, 95% CI 2.14–19.33), and embolic events during antimicrobial therapy (OR 12.14, 95% CI 2.11–71.89). Conclusions: An elevated CRP level at hospital admission and vegetation length at diagnosis were strong predictors of in-hospital mortality in IE, independent of other prognostic parameters, specifically taking into account patient characteristics and complications during therapy. Keywords: Infective endocarditis, C-reactive protein, Echocardiography, Mortality