Background: There are few studies on the histologic findings in native infective endocarditis, especially regarding mimics of autoimmune valvulitis. Methods: We prospectively studied 106 surgical specimens from 95 patients with a clinical diagnosis of infective endocarditis on native valves, and compared gross and histologic findings with culture results, underlying valve disease, risk factors and time interval from symptom onset to surgical intervention. Results: There were 41 (39%) aortic, 33 (31%) mitral, 9(9%) tricuspid, 1(.9%) pulmonic and 11 (10%) multiple valve replacements. Underlying valve disease was present in 26 (27%) patients (non-calcified bicuspid aortic valve, 10 (38%) cases; mitral valve prolapse, 5 (19%) cases; calcified trileaflet aortic valve, 5 (19%) cases; calcified bicuspid aortic valve, 2 (8%) cases; post-rheumatic mitral valve disease, 2 (8%) cases; hypertrophic cardiomyopathy-related mitral valve disease, 1 (4%) case, trileaflet aortic insufficiency 1 (4%) case) and associated with streptococcal infection (p =.001). Absence of underlying valve disease was associated with intravenous drug abuse (p =.01) and dialysis dependent renal disease (p =.006). Intravenous drug abuse was associated with staphylococcal infection (p =.03). Vegetations were present in 80 (75%) of cases, and on the nonflow surface of the valve in 65 (81%) of these. Gram-stain positivity and neutrophilic microabscesses were associated with staphylococcal infection (p =.03). Epithelioid macrophages with palisading features mimicking necrobiotic granulomas were seen in 42 (40%) valves and more frequently associated with streptococcal infection (p =.03). As expected, the presence of valve necrosis and acute inflammation decreased with an increase in time with respect to symptomatic onset. Conclusion: Histologic findings that mimic autoimmune inflammation are frequent in infective endocarditis and associated with streptococcal infection. Risk factors for infective endocarditis include calcific valve disease. (C) 2014 Elsevier GmbH. All rights reserved.