Objective: A simple and widely available test is needed to monitor the response to the treatment and predict adverse outcomes in patients with infective endocarditis (IE). We aimed to detect the role of C-reactive protein (CRP) level in the prognosis of IE.Materials and Methods: The patients diagnosed as probable or definite IE between 2015 and 2016 from five medical centers were included in the study. Clinical and laboratory features of the patients recorded on previously prepared forms retrospectively. Comparison of CRP levels between survived and dead patients were made by repeated-measures variance analysis. Receiver operating characteristic (ROC) curves at baseline, the first, second, third and fourth week of antimicrobial treatment were constructed to explain the ability of CRP level to predict mortality. Multivariate analysis was performed to predict the risk factors for mortality. Results: In total, 111 cases of IE were included. Serum CRP levels were higher in patients with mortality at every measurement. Comparing baseline CRP, lower than a double or triple decrease of serum CRP level at the third or fourth week of treatment or any increase under treatment were related to mortality. According to the ROC curve analysis, the highest overall accuracy in death prediction was at the fourth week CRP level (c=0.74); the CRP level of ≥50 mg/L was 86% sensitive and 78% specific to predict mortality. The presence of chronic renal failure (OR 14.386) and the fourth week CRP level (OR 1.016) were independent risk factors in terms of mortality. Conclusion: Being an easily performed and widely available test, CRP is a useful tool to follow up the response to the treatment and predict outcome among patients with IE. In the fourth week of treatment, a CRP level of ≥50 mg/L should be regarded as an alarming sign of poor outcome and should lead to investigation and appropriate management of complications.