Community-acquired culture-negative endocarditis represents a distinct subpopulation that clinicians face difficulties to manage due to lack of germ-guided antibiotic therapy. We studied the clinical characteristics, in-hospital mortality, and short-term prognosis of patients with culture-negative endocarditis. We performed a observational retrospective endocarditis. In total, 114 episodes of definite endocarditis according to Duke criteria, were studied (2014–2019). We compared the clinical, laboratory, and echocardiography characteristics and the complications and survival rates of patients with culture-negative and culture-positive endocarditis. Statistical analysis was performed by SPSS IBM. Culture-negative endocarditis occurred in 76/114 (66%) episodes. Compared with the culture-positive endocarditis patients, the time elapsed between first symptoms and admission was lower in patients with culture-negative endocarditis, with a mean of 20 days vs. 30 days in culture-positive group ( P < 0.05), and these patients also had lower C-reactive protein levels at admission (99 vs. 120 mg/dL) ( P < 0.05). The hospital length of stay was not different between the two groups with a mean of days of hospitalization of 27 days. However, in-hospital mortality rates were higher in culture-negative versus culture-positive patients (15% vs. 11% mortality rate) P < 0.05. As for complication, rates severe sepsis and vascular complication (stroke, splenic infarction) were higher in the negative culture group, with 7.9% vs. 3.1% in the positive culture endocarditis group P < 0.05. Culture-negative endocarditis patients presented with lower levels of C-reactive protein at admission and required less time for hospital admission, however presented a higher rate of in-hospital mortality and complications compared to culture-positive endocarditis patients.