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Background: Infective endocarditis (IE) is a continuously evolving disease with a high mortality rate despite different advances in treatment. In Ethiopia, there is a paucity of data regarding IE. Therefore, this study is aimed at assessing IE-related in-hospital mortality and characterization of IE patients based on their microbiological, clinical features, and management profiles in the Ayder Comprehensive Specified Hospital (ACSH). Methods: We conducted a hospital-based prospective follow-up study with all consecutive sampling techniques for suspected infective endocarditis patients admitted to ACSH from January 2020 to February 2022. Echocardiography was performed, and three sets of blood samples for blood culture were taken as per the standard protocol. We also performed isolation of microbial etiologies and antimicrobial susceptibility tests. The data was analyzed using STATA version 16. Stepwise logistic regression was run to identify predictors of in-hospital mortality. Effects were measured through the odds ratio at the 5% level of significance. Results: Seventy-four cases of suspected infective endocarditis were investigated; of these, 54 episodes fulfilled modified Duke's criteria. Rheumatic heart disease (RHD) (85.2%) was the most common underlying heart disease. Murmur (94.4%), fever (68.5%), and pallor (57.4%) were the most common clinical findings. Vegetation was present in 96.3% of episodes. Blood culture was positive only in 7 (13%) episodes. Complications occurred in 41 (75.9%) cases, with congestive heart failure being the most common. All patients were managed medically, with no surgical intervention. The in-hospital mortality was 14 (25.9%). IE-related in-hospital mortality was significantly associated with surgery recommendation and myalgia clinical symptoms. Conclusion: IE occurred relatively in a younger population, with RHD as the most common underlying heart disease. There was a high rate of culture-negative endocarditis, and the majority of patients were treated empirically. Mortality was high. The establishment of cardiac surgery and strengthening microbiology services should be given top priority. [ABSTRACT FROM AUTHOR]